(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(19) World Intellectual Property
Organization
International Bureau
(43) International Publication Date
28 April 2005 (28.04.2005)
PCT
(10) International Publication Number
WO 2005/037273 Al
(51) International Patent Classification^: A61K 31/4184,
31/428, C07D 401/12, 405/14, 401/14, 417/12, 409/14,
413/14, A61P 35/00
(21) International Application Number:
PCT/US2004/034179
(22) International Filing Date: 15 October 2004 (15,10.2004)
(25) Filing Language:
(26) Publication Language:
English
English
(30) Priority Data:
60/511,966
16 October 2003 (16.10.2003) US
(71) Applicant (for all designated States except US)i CHI-
RON CORPORATION [US/US]; 4560 Horton Street,
Emeryville, CA 94608-2916 (US).
(72) Inventors; and
(75) Inventors/Applicants (for US only): RAMURTHY,
Savithri [IN/US]; 4560 Horton Street, Emeryville, CA
94608-2916 (US). SUBRAMANIAN, Sharadha [IN/US];
4560 Horton Street, Emeryville, CA 94608-2916 (US).
VERHAGEN, Joelle [US/US]; 4560 Horton Street,
Emeryville, CA 94608-2916 (US). POON, Daniel, J.
[US/US]; 4560 Horton Street, Emeryville, CA 94608-2916
(US). HANSEN, Teresa [US/US]; 4560 Horton Street,
Emeryville, CA 94608-2916 (US). SHAFER, Cynthia
[US/US]; 4560 Horton Street, Emeryville, CA 94608-2916
(US). McBRIDE, Christopher [US/US]; 4560 Horton
Street, Emeryville, CA 94608-2916 (US). LEVINE,
Barry, H. [US/US]; 4560 Horton Street, Emeryville,
CA 94608-2916 (US). COSTALES, Abran [US/US];
4560 Horton Street, Emeryville, CA 94608-2916 (US).
RENHOWE, Paul, A. [US/US]; 4560 Horton Street,
Emeryville, CA 94608-2916 (US).
(74) Agent: SHELTON, Dennis, K.; Christensen O'Connor
Johnson Kindness PLLC, Suite 2800, 1420 Fifth Avenue,
Seattle, WA 98101 (US).
(81) Designated States (unless otherwise indicated, for every
kind of national protection available): AE, AG, AL, AM,
AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
PH, PL, FT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
ZW.
(84) Designated States (unless otherwise indicated, for every
kind of regional protection available): ARIPO (BW, GH,
GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
FR, GB, GR, HU, IE, IT, LU, MC, NL, PL, PT, RO, SE, SI,
SK, TR), OAPI (BE, BJ, CF, CG, CI, CM, GA, GN, GQ,
GW, ML, MR, NE, SN, TD, TG).
Published:
— with international search report
For two- letter codes and other abbreviations, refer to the "Guid-
ance Notes on Codes and Abbreviations " appearing at the begin-
ning of each regular issue of the PCT Gazette.
(54) Title: SUBSTITUTED BENZAZOLES AND USE THEREOF AS INHIBITORS OF RAF KINASE
O
i?5
o
(I)
(57) Abstract: New substituted benzazole
compounds of formula (I), compositions and
methods of inhibition of Raf kinase activity in a
human or animal subject are provided. The new
compounds compositions may be used either alone
or in combination with at least one additional agent
for the treatment of a Raf kinase mediated disorder,
such as cancer.
wo 2005/037273
PCT/US2004/034179
SUBSTITUTED BENZAZOLES AISID USE THEREOF AS INHIBITORS OF RAF KINASE
FIELD OF THE INVENTION
5 The present invention relates to new substituted benzazole compounds and
pharmaceutically acceptable salts, esters or prodrugs thereof, compositions of the new
compoimds together with pharmaceutically acceptable carriers, and uses of the new
compounds, either alone or in combination with at least one additional therapeutic agent,
in the prophylaxis or treatment of cancer.
1 0 BACKGROUND OF THE INVENTION
The Raf serine/threonine kinases are essential components of the Ras/Mitogen-
Activated Protein Kinase (MAPK) signaling module that controls a complex
transcriptional program in response to extemal cellular stimuli. Raf genes code for highly
conserved serine-threonine-specific protein kinases which are known to bind to the ras
1 5 oncogene. They are part of a signal transduction pathway believed to consist of receptor
tyrosine kinases, p21 ras, Raf protein kinases, Mekl (ERK activator or MAPKK) kinases
and ERK (MAPK) kinases, which ultimately phosphorylate transcription factors. In this
pathway Raf kinases are activated by Ras and phosphorylate and activate two isoforms of
Mitogen- Activated Protein Kinase ECinase (called Mekl and Mek2), that are dual
20 specificity threonine/tyrosine kinases. Both Mek isoforms activate Mitogen Activated
Kinases 1 and 2 (MAPK, also called Extracellular Ligand Regulated Kinase 1 and 2 or
Erkl and Erk2). The MAPKs phosphorylate many substrates including transcription
factors and in so doing set up their transcriptional program. Raf kinase participation in
the Ras/MAPK pathway influences and regulates many cellular functions such as
25 proliferation, differentiation, survival, oncogenic transformation and apoptosis.
Both the essential role and the position of Raf in many signaling pathways have
been demonstrated from studies using deregulated and dominant inhibitory Raf mutants
in mammalian cells as well as from studies employing biochemical and genetic
techniques model organisms. In many cases, the activation of Raf by receptors that
30 stimulate cellular tyrosine phosphorylation is dependent on the activity of Ras, indicating
that Ras functions upstream of Raf. Upon activation, Raf-1 then phosphorylates and
activates Mekl, resulting in the propagation of the signal to downstream effectors, such
as MAPK (mitogen-activated protein kinase) (Crews et al. (1993) Cell 74:215). The Raf
wo 2005/037273
PCT/US2004/034179
serine/threonine kinases are considered to be the primary Ras effectors involved in the
proliferation of animal cells (Avruch et al. (1994) Trends Biochem, Sci. 19:279).
Raf kinase has three distinct isoforms, Raf-1 (c-Raf), A-Raf, and B-Raf,
distinguished by their ability to interact with Ras, to activate MAPK kinase pathway,
5 tissue distribution and sub-cellular localization (Marias et. aL, Biochem. X 351: 289-305,
2000; Weber et al.. Oncogene 19:169-176, 2000; Pritchard et al., Mol Cell Biol
15:6430-6442, 1995). Raf kinases are activated by Ras and phosphorylate and activate
two isoforms of Mitogen- Activated Protein Kinase Kinase (called Mekl and Mek2) that
are dual specificity threonine/tyrosine kinases. Both Mek isoforms activate Mitogen
10 Activated Kinases 1 and 2 (MAPK, also called Extracellular Ligand Regulated Kinase 1
and 2 or Erkl and Erk2). The MAPKs phosphorylate many substrates including cytosolic
proteins and ETS family of transcription factors. Raf kinase participation in the
Ras/MAPK pathway influences and regulates many cellular functions such as
proliferation, differentiation, survival, cell cycle progression and apoptosis.
15 Activating mutation of one of the Ras genes can be seen in -20% of all tumors
and the Raf/MEK/ERK pathway is activated in -30% of all tumors (Bos et. al.. Cancer
Res. 49:4682-4689, 1989) (Hoshino et. al.. Oncogene 18:813-822, 1999). Recent studies
have shown that B-Raf mutation in the skin nevi is a critical step in the initiation of
melanocytic neoplasia (Pollock et. al.. Nature Genetics 25:1-2, 2002). Furthermore, most
20 recent studies have emerged that activating mutation in the kinase domain of B-Raf
occurs in -66% of melanomas, 12% of colon carcinoma and 14% of liver cancer (Davies
et. al., Nature 417:949-954, 2002) (Yuen et. aL, Cancer Research 62:6451-6455, 2002)
(Brose et. al.. Cancer Research 62:6997-7000, 2002).
Inhibitors of Raf/MEK/ERK pathway at the level of Raf kinases can potentially be
25 effective as therapeutic agents against tumors with over-expressed or mutated receptor
tyrosine kinases, activated intracellular tyrosine kinases, tumors with aberrantly
expressed Grb2 (an adapter protein that allows stimulation of Ras by the Sos exchange
factor) as well as tumors harboring activating mutations of Raf itself In the early clinical
trails inhibitor of Raf-1 kinase that also inhibit B-Raf have shown promise as therapeutic
30 agents in cancer therapy (Crump, Current Pharmaceutical Design 8: 2243-2248, 2002;
Sebastien et. aL, Current Pharmaceutical Design 8: 2249-2253, 2002). In addition, an
orally administered Raf kinase inhibitor that inhibits both B-Raf and C-Raf,
BAY 43-9006, is currently undergoing worldwide clinical evaluation in phase I and II
wo 2005/037273
PCT/US2004/034179
clinical studies in patients with a variety of malignancies, including melanomas (Tuveson
et aL, Cancer Cell 4: 95-98, 2003).
Disruption of Raf expression in cell lines through the application of RNA
antisense technology has been shown to suppress both Ras and Raf-mediated
5 tumorigenicity (Kolch et al.. Nature 349:416-428, 1991; Monia et al., Nature Medicine
2(6):668-675, 1996), In recent studies, reduction in B-Raf levels with RNA interference
in melanoma cells resulted in a profound inhibition of the MAP kinase cascade,
diminished proliferative capacity, and the inability to support anchorage-independent cell
growth (Tuveson et al.. Cancer Cell 4: 95-98, 2003).
10 Several Raf kinase inhibitors have been described as exhibiting efficacy m
inhibiting tumor cell proliferation in vitro and/or in vivo assays (see, e.g., U.S. Pat. Nos,
6,391,636, 6,358,932, 6,037,136, 5,717,100, 6,458,813, 6,204,467, and 6,268,391). Other
patents and patent applications suggest the use of Raf kinase inhibitors for treating
leukemia (see, e.g., U.S. Patent Nos. 6,268,391, and 6,204,467, and pubUshed U.S. Patent
15 Application Nos. 20020137774; 20020082192; 20010016194; and 20010006975), or for
treating breast cancer (see, e.g., U.S. Patent Nos. 6,358,932, 5,717,100, 6,458,813,
6,268,391, and 6,204,467, and published U.S. Patent Application No, 20010014679).
Certain benzazole compoimds and their use as Raf kinase inhibitors are disclosed
in WO03082272 and published U.S. Patent Application No. 20040122237 AL However,
20 these published applications do not disclose the carboxamide compounds of the present
New substituted benzazole compoimds and pharmaceutically acceptable salts
thereof or esters having a solubility enhancing moieties or prodrugs thereof are provided
25 of the formula (I) :
wherein, Xi and X3 are independently selected from N, -NR4-, -O- or -S-, wherein
R4 is hydrogen or loweralkyl, provided that at least one of Xi and X3 must be N or -NR4-;
invention.
SUMMARY OF THE INVENTION
-3-
wo 2005/037273
PCT/US2004/034179
X2 is -NH- or -(CH2)m- , wherein m is 0, 1 , 2, 3 or 4;
Ai is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl,
polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryU or
heteroarylheteroaryl;
Rj is hydrogen or substituted or unsubstituted loweralkyl, alkoxyalkyl,
loweralkyloxy, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
alkyloxyalkylheterocycloalkyl, heteroarylalkyl, cycloalkyloweralkyl, heterocycloalkyl-
loweralkyU loweralkylheterocycloalkyl, arylloweralkyl, heteroarylloweralkyl, alkyloxy-
alkylheterocycloloweralkyl, or heteroarylloweralkyl;
R2 is hydrogen or loweralkyl;
each R3 and R3' are independently selected from hydrogen, halogen, hydroxy,
cyano, loweralkyl, or loweralkoxy; and
p and q are independently 0, 1, 2 or 3; or
a pharmaceutically acceptable salt, ester or prodrug thereof.
In other embodiments, new substituted benzimidazole compoimds are provided of
the formula (11) :
wherein and X2, Ai, Ri, R2, R3, and R4 are as defined above; or
a pharmaceutically acceptable salt, ester or prodrug thereof.
In other embodiments, new substituted benzazole compounds are provided of the
(11)
formula (III):
(III)
wherein and Xi, X2, Ai, Ri, R2, and R3 are as defined above; or
a pharmaceutically acceptable salt, ester or prodrug thereof.
wo 2005/037273
PCT/US2004/034179
In other embodiments, new substituted benzazole compotinds are provided of the
formula (IV):
wherein Xi, A^, R^, R2, and R3 are as defined above; or
a pharmaceutically acceptable salt, ester or prodrug thereof.
In yet other embodiments, new substituted benzimidazole compounds are
provided of the formula (V):
R7 Rs
wherein Rj, R2> R3 and R4 are as defined above; and
R5, R6, R7, Rg and R9 are independently selected firom hydrogen, halo,
loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy, haloloweralkyloxy,
loweralkylthio, haloloweralkylthio, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl; or
a pharmaceutically acceptable salt, ester or prodrug thereof.
In yet other embodiments, new substituted benzimidazole compounds are
provided of the formula (VI):
wherein R2, R3, R4 R5, Re. R7. Rg ^9 defined above;
wo 2005/037273
PCT/US2004/034179
nis 0, 1, 2, 3 or 4;
RjQ, and R12 are independently selected from hydrogen, halo, loweralkyl,
haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkyl-
snlfonyU haloloweralkylsulfonyl, and substituted or unsubstituted cycloalkyl,
5 heterocycloalkyl, aryl, or heteroaryl; and
Rl I is hydrogen, , loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy,
haloloweralkyloxy, loweralkyloxyloweralkyl, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl; or
a pharmaceutically acceptable salt, ester or prodrug thereof.
10 In other aspects, the present invention provides methods for treating Raf related
disorders in a human or animal subject in need of such treatment comprising
administering to said subject an amount of a compoimd of formula (I), (II), (III), (IV), (V)
or (VI) effective to reduce or prevent tumor growth in the subject.
In yet other aspects, the present invention provides methods for treating Raf
15 related disorders in a hmnan or animal subject in need of such treatment comprising
administering to said subject an amount of a compound of formula (I), (II), (III), (IV), (V)
or (VI) effective to reduce or prevent tumor growth in the subject in combination with at
least one additional agent for the treatment of cancer.
In yet other aspects, the present invention provides therapeutic compositions
20 comprising at least one compound of formula (I), (II), (III), (IV), (V) or (VI) in
combination with one or more additional agents for the treatment of cancer, as are
commonly employed in cancer therapy.
In yet other aspects, the present invention provides a compound of formula (I),
(II), (III), (IV), (V) or (VI) for use as a pharmaceutical. The present invention further
25 provides for the use of a compound of formula (I), (II), (III), (IV), (V) or (VI) in the
manufacture of a medicament for the treatment of cancer.
The compounds of the invention are useful in the treatment of cancers, including
malignant melanoma, papillary thyroid cancer, cholangiocarcinoma, gallbladder
carcinoma, colorectal cancer, Ixmg cancer, pancreatic cancer, leukemias, prostate cancer,
30 ovarian cancer, breast cancer and limg cancer.
The invention further provides compositions, methods of use, and methods of
manufacture as described in the detailed description of the invention.
-6-
wo 2005/037273
PCT/US2004/034179
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
In accordance with one aspect of the present invention, new substituted benzazole
compounds and pharmaceutically acceptable salts, esters or prodrugs thereof are provided
of the formula (I):
wherein, Xi and X3 are independently selected from N, -NR4-, -O- or -S-, wherein
R4 is hydrogen or loweralkyU provided that at least one of Xi and X3 must be N or -NR4-;
X2 is -NH- or -(CH2)m- , wherein m is 1, 2, 3 or 4;
Ai is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl,
10 polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, or
heteroarylheteroaryl;
is hydrogen or substituted or uasubstituted loweralkyl, alkoxyalkyl,
loweralkyloxy, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
alkyloxyalkylheterocycloalkyl, heteroarylalkyl, cycloalkyloweralkyl, heterocycloalkyl-
15 loweralkyU loweralkylheterocycloalkyl, arylloweralkyl, heteroarylloweralkyl, alkyloxy-
alkylheterocycloloweralkyl, or heteroarylloweralkyl;
R2 is hydrogen or loweralkyl;
each R3 and R3' are independently selected from hydrogen, halogen, hydroxy,
cyano, loweralkyl, or loweralkoxy; and
20 p and q are independently 0, 1, 2 or 3; or
a pharmaceutically acceptable salt, ester or prodrug thereof
In some aspects of the invention, Xi in formula (I) is -NR4-. Thus, in some
embodiments, new substituted benzimidazole compounds are provided of the formula
R2
(I)
(11):
25
(II)
-7-
wo 2005/037273
PCT/US2004/034179
wherein and X2, Aj, R^, R2, R3, and R4 are as defined above; or
a pharmaceutically acceptable salt, ester or prodrug thereof.
In other embodiments of the invention, X3 is N and X4, is -CH- in formula (I).
Thus, in some aspects the invention provides new substituted benzazole compounds of
the formula (III):
R2
I ^
N O
(III)
wherein and Xi, X2, Aj, Rj, R2, and R3 are as defined above; or
a pharmaceutically acceptable salt, ester or prodrug thereof.
In other embodiments of the invention, X2 is -NH- in formula (I). Thus, in some
aspects, new substituted benzazole compovmds are provided of the formula (IV):
R2
TT T
O
R3 (IV)
wherein Xi, A^, R^, R2, and R3 are as defined above; or
a pharmaceutically acceptable salt, ester or prodrug thereof
In yet other embodiments of the invention, Xi -NR4-, X2 is -NH-, X3 is N, X4 is
■CH- and Ai is in formula (I) has the structure:
wherein R5, R5, Ry, R3 and R9 are independently selected from hydrogen, halo,
loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy, haloloweralkyloxy,
loweralkylthio, haloloweralkylthio, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl. Thus, in some aspects, new substituted
benzimidazole compounds are provided of the formula (V):
wo 2005/037273
PCT/US2004/034179
R7 Rs
(V)
wherein R^, R2, R3 and R4 are as defined above; and
R55 Rg, R75 R3 and R9 are independently selected firom hydrogen, halo,
loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy, haloloweralkyloxy,
loweralkylthio, haloloweralkylthio, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl; or
a pharmaceutically acceptable salt, ester or prodrug thereof. In representative, but
non-limiting embodiments, R5, R5, Ry, R3 and R9 may be independently selected from,
for example, hydrogen, chloro, fluoro, methyl, ethyl, propyl, z^o-propyl, butyl, ^e^^butyl,
methyloxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, acetyl, and substituted
or imsubstituted phenyl, phenyloxy, furyl, tetrahydrofuranyl, tetrahydropyranyl,
pyridinyl, trifluoromethylpiperidinyl, thiophenyl, piperazinyl, and morpholinyl.
In yet other embodiments, Ri in formula (V) has the structure:
wherein n is 0, 1, 2, 3 or 4;
r is 1 or 2;
X4 is -CH- or N
RlO, and are independently selected from hydrogen, halo, loweralkyl,
haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkyl-
sulfonyl, haloloweralkylsulfonyl, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl; and
Rll is hydrogen, loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy,
haloloweralkyloxy, loweralkyloxyloweralkyl, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl. In some presently preferred embodiments, r is 1 and
wo 2005/037273
PCT/US2004/034179
X4 is N. Thus, in some aspects the invention provides new substituted benzimidazole
concipounds are provided of the formula (VI):
R7
wherein R2, R35 R45 R5, Rg, Ry? Rg aJid R9 are as defined above;
n is 0, 1, 2, 3 or 4;
KlQ, and R12 are independently selected from hydrogen, halo, loweralkyl,
haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkyl-
sulfonyl, haloloweralkylsulfonyl, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl; and
Rj 1 is hydrogen, , loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy,
haloloweralkyloxy, loweralkyloxyloweralkyl, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl; or
a pharmaceutically acceptable salt, ester or prodrug thereof.
In another aspect, the present invention provides methods of treating human or
animal subjects suffering from a Raf related disorder, such as cancer. Thus, the present
invention provides methods of treating a hxoman or animal subject in need of such
treatment comprising administering to the subject a therapeutically effective amount of a
compoxmd of formula (I), (II), (III), (IV), (V) or (VI) above, either alone or in
combination with other anticancer agents.
In other aspects, the present invention provides methods for treating Raf related
disorders in a human or animal subject in need of such treatment comprising
administering to said subject an amount of a compound of formula (I), (II), (III), (IV) or
(V) effective to reduce or prevent tumor growth in the subject.
In yet other aspects, the present invention provides methods for treating Raf
related disorders in a human or animal subject in need of such treatment comprising
administering to said subject an amount of a compound of formula (I), (II), (III), (IV) or
(V) effective to reduce or prevent tumor growth in the subject in combination with at
-10-
wo 2005/037273
PCT/US2004/034179
least one additional agent for the treatment of cancer. A nxamber of suitable anticancer
agents to be used as combination therapeutics are contemplated for use in the methods of
the present invention. Indeed, the present invention contemplates, but is not limited to,
administration of numerous anticancer agents such as: agents that induce apoptosis;
polynucleotides (e.g., ribozymes); polypeptides (e.g., enzymes); drugs; biological
mimetics; alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones;
platinum compounds; monoclonal antibodies conjugated with anticancer drugs, toxins,
and/or radionuclides; biological response modifiers (e.g. interferons [e.g. IFN-a, etc.] and
interleukins [e.g. IL-2, etc.], etc.); adoptive immunotherapy agents; hematopoietic growth
factors; agents that induce tumor cell differentiation (e.g. all-trans-retinoic acid, etc.);
gene therapy reagents; antisense therapy reagents and nucleotides; tumor vaccines;
inhibitors of angiogenesis, and the like. Numerous other examples of chemotherapeutic
compounds and anticancer therapies suitable for coadministration with the disclosed
compounds of formula (I), (II), (III), (IV), (V) or (VI) are known to those skilled in the
art.
In preferred embodiments, anticancer agents to be used in combination with
compounds of the present invention comprise agents that induce or stimulate apoptosis.
Agents that induce apoptosis include, but are not Umited to, radiation; kinase inhibitors
(e.g., epidermal growth factor receptor [EGFR] kinase inliibitor, vascular endothelial
growth factor receptor [VEGFR] kinase inhibitor, fibroblast growth factor receptor
[FGFR] kinase inhibitor, platelet-derived growth factor receptor [PGFR] I kinase
inhibitor, and Bcr-Abl kinase inhibitors such as Gleevec® [imatinib mesylate or STI-
571]); antisense molecules; antibodies [e.g., Herceptin® anti-HER monoclonal antibody
and Rituxan® anti-CD20 monoclonal antibody]; anti-estrogens [e.g., raloxifene and
tamoxifen]; anti-androgens [e.g., flutamide, bicalutamide, finasteride, amino-
glutethamide, ketoconazole, and corticosteroids]; cyclo oxygenase 2 (COX-2) inhibitors
[e.g., Celecoxib®, meloxicam, NS-398, and non-steroidal antiinflammatory drugs
(NSAIDs)]; and cancer chemotherapeutic drugs [e.g., irinotecan (Camptosar®), CPT-11,
fludarabine (Fludara®), dacarbazine (DTIC®), dexamethasone, mitoxantrone, Mylotarg®,
VP- 16, cisplatin-um, 5-FU, doxrubicin, docetaxel (Taxotere® or taxol, dacarbazine,
aldesleukin, capecitabine, and Iressa® (gefitinib)]; cellular signaling molecules;
ceramides and cytokines; and staurosprine, and the like.
wo 2005/037273
PCT/US2004/034179
In some embodiments of this aspect of the invention, anticancer agents to be used
in combination with compoimds of the present invention include, for example,
dacarbazine, irinotecan, topotecan, gemcitabine, S-fluoroviracil, leucovorin carboplatin,
cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib,
5 anthracyclines, rituximab and trastuzumab
In other aspects, the present invention provides pharmaceutical compositions
comprising at least one compound of formula I, II, III, IV or V together with a
pharmaceutically acceptable carrier suitable for administration to a human or animal
subject, either alone or together with other anticancer agents.
10 In other aspects, the present invention provides methods of manufacture of
compounds of formula (I), (II), (III), (IV), (V) or (VI) as described herein.
In yet other aspects, the present invention provides compoxmds which are
inhibitors of the enzyme raf kinase. Since the enzyme is a downstream effector of p2iras^
the instant inhibitors are useful in pharmaceutical compositions for human or veterinary
15 use where inhibition of the raf kinase pathway is indicated, e.g., in the treatment of
tumors and/or cancerous cell grov^h mediated by raf kinase. In particular, the
compounds are useful in the treatment of human or animal, e.g., murine cancer, since the
progression of these cancers is dependent upon the ras protein signal transduction cascade
and therefore is susceptible to treatment by interruption of the cascade by inhibiting raf
20 kinase activity. Accordingly, the compoimds of the invention are useful in treating
cancers, such as, for example, malignant melanoma, papillary thyroid cancer,
cholangiocarcinoma, gallbladder carcinoma, colorectal cancer, lung cancer, pancreatic
cancer, leukemias, prostate cancer, ovarian cancer, breast cancer and lung cancer.
"Raf inhibitor" is used herein to refer to a compound that exliibits an IC50 with
25 respect to Raf Kinase activity of no more than about 100 ^iM and more typically not more
than about 50 juM, as measured in the Raf/Mek Filtration Assay described generally
hereinbelow. Preferred isoforms of Raf Kinase in which the compounds of the present
invention will be shown to inhibit, include A-Raf, B-Raf, and C-Raf (Raf-1). "IC50" is
that concentration of inhibitor which reduces the activity of an enzyme (e.g., Raf kinase)
30 to half-maximal level. Representative compounds of the present invention have been
discovered to exhibit inhibitory activity against Raf. Compounds of the present invention
preferably exhibit an IC50 with respect to Raf of no more than about 10 |aM, more
preferably, no more than about 5 laM, even more preferably not more than about 1 |aM,
-12-
wo 2005/037273
PCT/US2004/034179
and most preferably, not more than about 200 nM, as measixred in the Raf kinase assays
described herein.
As used herein, the term "benzazoles" includes benzimidazoles, benzothiazoles
and benzoxazoles.
5 The phrase "alkyl" refers to alkyl groups that do not contain heteroatoms. Thus
the phrase includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl,
pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The phrase also
includes branched chain isomers of straight chain alkyl groups, including but not limited
to, the following which are provided by way of example: — CH(CH3)25
1 0 -CH(CH3)(CH2CH3), -CH(CH2CH3)2, -C(CH3)3, -C(CH2CH3)3, -CH2CH(CH3)2,
-CH2CH(CH3)(CH2CH3), -CH2CH(CH2CH3)2, -CH2C(CH3)3, -CH2C(CH2CH3)3.
-CH(CH3)CH(CH3)(CH2CH3), -CH2CH2CH(CH3)2, -CH2CH2CH(CH3)(CH2CH3),
-CH2CH2CH(CH2CH3)2, -CH2CH2C(CH3)3, -CH2CH2C(CH2CH3)3, -CH(CH3)CH2.
CH(CH3)2, -CH(CH3)CH(CH3)CH(CH3)2, -CH(CH2CH3)CH(CH3)CH(CH3)(CH2CH3),
15 and others. The phrase also includes cyclic alkyl groups such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted with
straight and branched chain alkyl groups as defined above. Thus the phrase alkyl groups
includes primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups.
Preferred alkyl groups include straight and branched chain alkyl groups and cyclic alkyl
20 groups having 1 to 12 carbon atoms.
As used herein "loweralkyl" includes both substituted or unsubstituted straight or
branched chain alkyl groups having from 1 to 6 carbon atoms. Representative loweralkyl
groups include, for example, methyl, ethyl, propyl, isopropyl, ?iz-butyl, tert-butyl,
neopentyl, trifluoromethyl, pentafluoroethyl and the like. Loweralkyl groups may be
25 substituted, such as v^th halo, hydroxy, amino, nitro and/or cyano groups, and the like.
Representative of halo-substituted and hydroxy-substituted loweralkyl include
chloromethyl, trichloromethyl, fluoromethyl, trifluoromethyl, chloroethyl, fluoroethyl,
hydroxyethyl, perfluoropentyl, perflurorheptyl and the like. Other suitable substituted
loweralkyl moieties include, for example, aralkyl, aminoalkyl, aminoaralkyl,
30 carbonylaminoalkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl, aralkylcarbonyl-
aminoalkyl, aminoalkoxy alkyl and arylaminoalkyl.
-13-
wo 2005/037273
PCT/US2004/034179
"Loweralkoxy" as used herein refers to RO- wherein R is loweralkyl.
Representative examples of loweralkoxy groups include methoxy, ethoxy, iT-butoxy,
trifluoromethoxy and the like.
As used herein, the term "halogen" or "halo" refers to chloro, bromo, fluoro and
iodo groups. "Haloalkyl" refers to an alkyl radical substituted with one or more halogen
atoms. The temi "haloloweralkyl" refers to a loweralkyl radical substituted with one or
more halogen atoms. The term "haloalkoxy" refers to an alkoxy radical substituted with
one or more halogen atoms. The term "haloloweralkoxy" refers to a loweralkoxy radical
substituted with one or more halogen atoms.
"Amino" refers herein to the group -NH2. The term "alkylamino" refers herein to
the group -NRR' where R and R' are each independently selected from hydrogen or a
lower alkyl. The term "arylamino" refers herein to the group -NRR' where R is aryl and
R is hydrogen, a lower alkyl, or an aryl. The term "aralkylamino" refers herein to the
group -NRR' where R is a lower aralkyl and R' is hydrogen, a loweralkyl, an aryl, or a
loweraralkyl.
The term amino acid refers to both alpha and beta amino acids having D- or
L-stereochemistry, and includes, but is not limited to, synthetic, non-natural amino acids
having side chains other than those foxmd in the 20 common amino acids. Non-natural
amino acids are commercially available or may be prepared according to US 5,488,131
and references therein. Amino acids may be further substituted to contain modifications
to their amino, carboxy, or side chain groups. These modifications include the numerous
protecting groups commonly used in peptide synthesis.
The term "alkoxyalkyl" refers to the group -alki-0-alk2 where alki is alkyl or
alkenyl, and alka is alkyl or alkenyl. The term "loweralkoxyalkyl" refers to an
alkoxyalkyl where alki is loweralkyl or loweralkenyl, and alki is loweralkyl or
loweralkenyl. The term "aryloxy alkyl" refers to tlie group ~alkyl-0-aryL The temi
"aralkoxyalkyl" refers to the group -alkylenyl-O-aralkyl, where aralkyl is a loweraralkyl.
The term "alkoxyalkylamino" refers herein to the group -NR-(alkoxyalkyl),
where R is typically hydrogen, loweraralkyl, or loweralkyl. The term
"aminoloweralkoxyalkyl" refers herein to an aminoalkoxyalkyl in which the alkoxyalkyl
is a loweralkoxyalkyl.
The term "aminocarbonyl" refers herein to the group -C(0)-NH2 . "Substituted
aminocarbonyl" refers herein to the group -C(0)-NRR' where R is loweralkyl and R is
-14-
wo 2005/037273
PCT/US2004/034179
hydrogen or a loweralkyl. The term "arylaminocarbonyr' refers herein to the group
-C(0)-NRR' where R is an aryl aad R is hydrogen, loweralkyl or aryl.
"aralkylaminocarbonyr' refers herein to the group -C(0)-NRR' where R is loweraralkyl
and R' is hydrogen, loweralkyl, aryl, or loweraralkyl.
5 "Aininosulfonyl" refers herein to the group -S(0)2-NH2. "Substituted
aminosulfonyl" refers herein to the group -S(0)2-NRR' where R is loweralkyl and R' is
hydrogen or a loweralkyl. The term "aralkylaminosulfonlyaryl" refers herein to the group
— aryl-S(0)2— NH-aralkyl, where the aralkyl is loweraralkyl.
"Carbonyl" refers to the divalent group — C(0)-.
10 "Carbonyloxy" refers generally to the group -~C(0)-0. Such groups include
esters, -C(0)-0-R, where R is loweralkyl, cycloalkyl, aryl, or loweraralkyl. The term
" carbonyloxy cycloalkyl" refers generally herein to both a "carbonyloxycarbocycloalkyl"
and a "carbonyloxyheterocycloalkyl", i.e., where R is a carbocycloalkyl or
heterocycloalkyl, respectively. The term "arylcarbonyloxy" refers herein to the group —
15 C(0)-0-aryl, where aryl is a mono- or polycyclic, carbocycloaryl or heterocycloaryl. The
term "aralkylcarbonyloxy" refers herein to the group -C(0)-0"-aralkyl, where the aralkyl
is loweraralkyl.
The term "sulfonyl" refers herein to the group -SO2-. "Alkylsulfonyr' refers to a
substituted sulfonyl of the structure -SO2R- in which R is alkyl. Alkylsulfonyl groups
20 employed in compoimds of the present invention are typically loweralkylsulfonyl groups
having from 1 to 6 carbon atoms in its backbone stmcture. Thus, typical alkylsulfonyl
groups employed in compounds of the present invention include, for example,
methylsulfonyl (i.e., where R is methyl), ethylsulfonyl (i.e., where R is ethyl),
propylsulfonyl (i.e., where R is propyl), and the like. The term "arylsulfonyl" refers
25 herein to the group -S02-aryl. The term "aralkylsulfonyl" refers herein to the group
-S02-aralkyl, in which the aralkyl is loweraralkyl. The term "sulfonamido" refers herein
to -SO2NH2.
As used herein, the term "carbonylamino" refers to the divalent group -NH-C(O)-
in which the hydrogen atom of the amide nitrogen of the carbonylamino group can be
30 replaced a loweralkyl, aryl, or loweraralkyl group. Such groups include moieties such as
carbamate esters (-NH-C(O)-O-R) and amides -NH-C(0)-0-R, where R is a straight or
branched chain loweralkyl, cycloalkyl, or aryl or loweraralkyl. The term
"loweralkylcarbonylamino" refers to alkylcarbonylamino where R is a loweralkyl having
-15-
wo 2005/037273
PCT/US2004/034179
from 1 to about 6 carbon atoms in its backbone structure. The term "arylcarbonylamino"
refers to group -NH-C(0)-R where R is an aryl. Similarly, the term
"aralkylcarbonylamino " refers to carbonylamino where R is a lower aralkyL As used
herein, the term "aminocarbonyl" refers to the divalent group -C(0)-NH- in which the
hydrogen atom of the amide nitrogen of the carbonylamino group can be replaced a
loweralkyl, aryl, or loweraralkyl group, as described above.
As used herein, the term "guanidino" or "guanidyl" refers to moieties derived
from guanidine, H2N-C(=NH)-NH2. Such moieties include those bonded at the nitrogen
atom carrying the formal double bond (the "2"-position of the guanidine, e.g.,
diaminomethyleneamino, (H2N)2C=NH-) and those bonded at either of the nitrogen
atoms carrying a formal single bond (the "1-" and/or "3 "-positions of the guandine, e.g.,
H2N-C(==NH)-NH-). The hydrogen atoms at any of the nitrogens can be replaced with a
suitable substituent, such as loweralkyl, aryl, or loweraralkyl.
As used herein, the term "amidino" refers to the moieties R-C(=N)-NR'- (the
radical being at the "N^" nitrogen) and R(NROC=N- (the radical being at the "N^"
nitrogen), where R and R' can be hydrogen, loweralkyl, aryl, or loweraralkyl.
"Cycloalkyl" refers to a mono- or polycyclic, heterocyclic or carbocyclic alkyl
substituent. Typical cycloalkyl substituents have from 3 to 8 backbone (i.e., ring) atoms
in which each backbone atom is either carbon or a heteroatom. The term
"heterocycloalkyl" refers herein to cycloalkyl substituents that have from 1 to 5, and more
typically from 1 to 4 heteroatoms in the ring structure. Suitable heteroatoms employed in
compounds of the present invention are nitrogen, oxygen, and sulftir. Representative
heterocycloalkyl moieties include, for example, morpholino, piperazinyl, piperadinyl and
the like, Carbocycloalkyl groups are cycloalkyl groups in which all ring atoms are
carbon. When used in connection with cycloalkyl substituents, the term "polycyclic"
refers herein to fused and non-ftised alkyl cyclic structures. Examples of such polycyclic
structures include bicyclic compounds having two bridgehead atoms coimected by three
or more arms. An example of a bicycUc structure is bicyclo[2.2.1] heptane, in which the
bridgehead atoms are connected by three arms respectively having two, two, and one
carbon atoms.
The term "substituted heterocycle" or "heterocyclic group" or heterocycle as used
herein refers to any 3- or 4-membered ring containing a heteroatom selected from
nitrogen, oxygen, and sulfur or a 5- or 6-membered ring containing from one to three
-16-
wo 2005/037273
PCT/US2004/034179
heteroatoms selected from the group consisting of nitrogen, oxygen, or sulfur; wherein
the 5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3 double
bonds; wherein the nitrogen and sulfur atom maybe optionally oxidized; wherein the
nitrogen and sulfur heteroatoms maybe optionally quartemized; and including any
bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or
another 5- or 6-membered heterocyclic ring independently defined above. The term
"heterocycle" thus includes rings in which nitrogen is the heteroatom as well as partially
and fully-saturated rings. Preferred heterocycles include, for example: diazapinyl, pyrryl,
pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazohdinyl, imidazoyl, imidazolinyl,
imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, N-methyl piperazinyl,
azetidinyl, N-methylazetidinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,
isoxazolyl, isoazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl,
isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl,
benzoxazolyl, furyl, thienyl, triazolyl and benzothienyl.
Heterocyclic moieties can be unsubstituted or monosubstituted or disubstituted
with various substituents independently selected from hydroxy, halo, oxo (C=0),
alkylimino (RN-=, wherein R is a loweralkyl or loweralkoxy group), amino, alkylamino,
dialkylamino, acylaminoalkyl, alkoxy, thioalkoxy, polyalkoxy, loweralkyl, cycloalkyl or
haloalkyl.
The heterocyclic groups may be attached at various positions as will be apparent
to those having skill in the organic and medicinal chemistry arts in conjimction with the
disclosure herein.
-17-
wo 2005/037273
PCT/US2004/034179
described herein.
5 Representative heterocyclics include, for example, imidazolyl, pyridyl,
piperazinyl, azetidinyl, thiazolyl, furanyl, triazolyl benzimidazolyl, benzothiazolyl,
benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, indolyl,
naphthpyridinyl, indazolyl, and quinolizinyl.
"Aryl" refers to optionally substituted monocyclic and polycyclic aromatic groups
1 0 having from 3 to 1 4 backbone carbon or hetero atoms, and includes both carbocy clic aryl
groups and heterocyclic aryl groups. Carbocyclic aryl groups are aryl groups in which all
rmg atoms in the aromatic ring are carbon. The term "heteroaryl" refers herein to aryl
groups having from 1 to 4 heteroatoms as ring atoms in an aromatic ring with the
remainder of the ring atoms being carbon atoms. When used in connection with aryl
15 substituents, the term "polycyclic aryl" refers herein to fused and non-ftised cyclic
structures in which at least one cyclic structure is aromatic, such as, for example,
benzodioxozolo (which has a heterocyclic structure fused to a phenyl group, i.e.,
^'"^^ , naphthyl, and the like. Exemplary aryl moieties employed as substituents in
compoxmds of the present invention include phenyl, pyridyl, pyrimidinyl, thiazolyl,
20 indolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyrazinyl, triazolyl, thiophenyl, furanyl,
quinolinyl, purinyl, naphthyl, benzothiazolyl, benzopyridyl, and benzimidazolyl, and the
like.
"Aralkyl" refers to an alkyl group substituted with an aryl group. Typically,
aralkyl groups employed in compounds of the present invention have from 1 to 6 carbon
25 atoms incorporated within the alkyl portion of the aralkyl group. Suitable aralkyl groups
-18-
wo 2005/037273
PCT/US2004/034179
employed in compounds of the present invention include, for example, benzyl, picolyl,
and the like.
Representative heteroaryl groups include, for example, those shown belov^. These
heteroaryl groups can be further substituted and may be attached at various positions as
will be apparent to those having skill in the organic and medicinal chemistry arts in
conjunction with the disclosure herein.
Representative heteroaryl groups include, for example, imidazolyl, pyridyl,
piperazinyl, azetidinyl, thiazolyl, triazolyl benzimidazolyl, benzothiazolyl, benzoxazolyl,
pyrazolyl and pyrazinyl.
The term "biaryl" refers to a group or substituent to vv^hich two aryl groups, vv^hich
are not condensed to each other, are bound. Exemplary biaryl compoimds include, for
example, phenylbenzene, diphenyldiazene, 4-methylthio- 1 -phenylbenzene, phenoxy-
benzene, (2-phenylethynyl)benzene, diphenyl ketone, (4-phenylbuta-l,3-diynyl)benzene,
phenylbenzylamine, (phenylmethoxy)benzene, and the like. Preferred optionally
substituted biaryl groups include: 2-(phenylamino)-N-[4-(2-phenylethynyl)phenyl]acet-
amide, 1 ,4-diphenylbenzene, N-[4-(2-phenylethynyl)phenyl]-2-[benzylamino]acetamide,
2-amino-N-[4-(2-phenylethynyl)phenyl]propanamide, 2-amino-N-[4-(2-phenylethynyl)-
phenyl] acetamide, 2-(cyclopropylamino)-N- [4-(2-phenylethynyl)phenyl] acetamide, 2-
-19-
wo 2005/037273
PCT/US2004/034179
(ethylamino)-N- [4-(2-phenylethynyl)phenyl] acetamide, 2- [(2-methylpropyl)amino] -N- [4-
(2-phenylethyayl)phenyl] acetamide, 5-phenyl-2H-benzo [d] 1 ,3 -dioxolene, 2-chloro- 1 -
methoxy-4-phenylbenzene, 2-[(imidazolylmethyl)amino]-N-[4-(2-phenylethynyl)phenyl]-
acetamide, 4-phenyl- 1 -phenoxybenzene, N-(2-ammoethyl) [4-(2-phenylethynyl)phenyl] -
carboxamide, 2- { [(4-fluorophenyl)methyl] amino } -N- [4-(2-phenylethynyl)phenyl] acet-
amide, 2- { [(4-methylphenyi)methyl] amino } -N- [4-(2-phenylethynyl)phenyl] acetamide, 4-
phenyl- 1 -(trifluoromethyl)ben2ene, 1 -butyl-4-phenylbenzene, 2-(cyclohexylaniino)-N-[4-
(2-phenylethynyl)phenyl]acetamide5 2-(ethylmethylamino)-N-[4-(2-phenylethynyl)-
phenyljacetamide, 2-(butylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide, N-[4-(2-
phenylethynyl)phenyl]-2-(4-pyridylamino)acetamide, N-[4-(2-phenylethynyl)phenyl]-2-
(quinuclidin-3-ylamino)acetamide, N-[4-(2-phenylethynyl)phenyl]pyrrolidin-2-ylcarbox-
amide, 2-amino-3 -methyl-N- [4-(2-phenylethynyl)phenyl]butanamide, 4-(4-phenylbuta-
1 ,3 -diyTiyl)phenylamine, 2-(dimethylamino)-N- [4-(4-phenylbuta- 1 ,3 -diynyl)phenyl] -
acetamide, 2-(ethylamino)-N-[4-(4-phenylbuta- 1 5 3-diynyl)phenyl]acetamide5 4-ethyl- 1 -
phenylbenzene, 1 - [4-(2-phenylethynyl)phenyl]ethan- 1 -one, N-(l -carbamoyl-2 -hydroxy-
propyl) [4-(4-phenylbuta- 1 ,3 -diynyl)phenyl] carboxamide, N- [4-(2-phenylethynyl)-
phenyljpropanamide, 4-methoxyphenyl phenyl ketone, phenyl-N-benzamide, (tert-
butoxy)-N-[(4-phenylphenyl)methyl]carboxamide, 2-(3-phenylphenoxy)ethane-
hydroxamic acid, 3-phenylphenyl propanoate, l-(4-ethoxyphenyl)-4-methoxybenzene,
and [4-(2-phenylethynyl)phenyl]pyrrole.
The term "heteroarylaryl" refers to a biaryl group where one of the aryl groups is a
heteroaryl group. Exemplary heteroarylaryl groups include, for example,
2-phenylpyridine, phenylpyrrole, 3-(2-phenylethynyl)pyridine, phenylpyrazole,
5-(2-phenylethynyl)-l ,3-dihydropyrimidine-2,4-dione, 4-phenyl- 1 52,3-thiadiazole, 2-(2-
phenylethynyl)pyrazine, 2-phenylthiophene5 phenylimidazole, 3-(2-piperazinylphenyl)-
furan, 3-(2,4-dichlorophenyl)-4-methylpyrrole, and the like. Preferred optionally
substituted heteroarylaryl groups include : 5-(2-phenylethynyl)pyrimidine-2-ylamine,
1 -methoxy-4-(2-thienyl)benzene, 1 -methoxy-3 -(2-thienyl)benzene, 5-methyl-2-phenyl-
pyridine, 5 -methyl-3 -phenylisoxazole, 2- [3 -(trifluoromethyl)phenyl] furan, 3 -fluoro-5 -
(2-furyl)-2-methoxy- 1 -prop-2-enylbenzene, (hydroxyimino)(5-phenyl(2-thienyl))-
methane, 5-[(4-methylpiperazinyl)methyl]-2-phenylthiophene, 2-(4-ethylphenyl)thio-
phene, 4-methylthio-l-(2-thienyl)benzene, 2-(3-nitrophenyl)thiophene, (tert-butoxy)-N-
-20-
wo 2005/037273
PCT/US2004/034179
[(5 -phenyl(3 -pyridyl))methyl] carboxamide, hydroxy-N- [(5-phenyl(3 -pyridyl))methyl] -
amide, 2-(phenylmethylthio)pyridine, and benzylimidazole.
The term "heteroarylheteroaryl" refers to a biaryl group where both of the aryl
groups are a heteroaryl group. Exemplary heteroarylheteroaryl groups include, for
example, 3-pyridylimidazole, 2-imidazolylpyrazine, and the like. Preferred optionally
substituted heteroarylheteroaryl groups include: 2-(4-piperazinyl-3-pyridyl)fiiran, diethyl-
(3 -pyrazin-2-yl(4-pyridyl))an3ine, and dimethyl {2- [2-(5 -methylpyrazin-2-yl)ethynyl] (4-
pyridyl)} amine.
"Optionally substituted" or "substituted" refers to the replacement of one or more
hydrogen atoms with a monovalent or divalent radical. Suitable substitution groups
include, for example, hydroxyl, nitro, amino, imino, cyano, halo, thio, sulfonyl,
thioamido, amidino, imidino, oxo, oxamidino, methoxamidino, imidino, guanidino,
sulfonamide, carboxyl, formyl, loweralkyl, haloloweralkyl, loweralkyamino,
haloloweralkylamino, loweralkoxy, haloloweralkoxy, loweralkoxyalkyl, alkylcarbonyl,
aminocarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl,
alkylthio, aminoalkyl, cyanoalkyl, aryl and the like. The term substituted and
unsubstituted, when introducing a list of substituents, is intended to apply to each
member of that list. For instance the phrase "substituted and unsubstituted aryl,
heteroaryl, or alkyl" and the phrase "substituted and unsubstituted aryl, heteroaryl, and
alkyl" is intended to specify aryl, heteroaryl, and alky groups that are each substituted or
xmsubstituted.
The substitution group can itself be substituted. The group substituted onto the
substitution group can be carboxyl, halo; nitro, amino, cyano, hydroxyl, loweralkyl,
loweralkoxy, aminocarbonyl, -SR, thioamido, -SO3H, -SO2R or cycloalkyl, where R is
typically hydrogen, hydroxyl or loweralkyl.
When the substituted substituent includes a straight chain group, the substitution
can occur either within the chain (e.g., 2-hydroxypropyl, 2-aminobutyl, and the like) or at
the chain terminus (e.g., 2-hydroxyethyl, 3-cyanopropyl, and the like). Substituted
substitutents can be straight chain, branched or cyclic arrangements of covalently bonded
carbon or heteroatoms.
As used herein, the term "carboxy-protecting group" refers to a carbonyl group
which has been esterified with one of the commonly used carboxylic acid protecting ester
groups employed to block or protect the carboxylic acid function while reactions
-21-
wo 2005/037273
PCT/US2004/034179
involving other functional sites of the compoimd are carried out. In addition, a carboxy
protecting group can be attached to a solid support whereby the compound remains
connected to the solid support as the carboxylate imtil cleaved by hydrolj^ic methods to
release the corresponding free acid. Representative carboxy-protecting groups include,
5 for example, loweralkyl esters, secondary amides and the like.
As used herein, the term "pharmaceutically acceptable salts" refers to the nontoxic
acid or alkaline earth metal salts of the compoimds of Formula L These salts can be
prepared in situ during the final isolation and purification of the compounds of Formula I,
or by separately reacting the base or acid functions with a suitable organic or inorganic
10 acid or base, respectively. Representative salts include but are not limited to the
following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate,
dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,
heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide,
15 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-napth-
alenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproionate, picrate,
pivalate, propionate, succinate, sulfate, tartrate, fhiocyanate, p-toluenesulfonate and
imdecanoate. Also, the basic nitrogen-containing groups can be quatemized with such
agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides,
20 and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long
chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides,
aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or
dispersible products are thereby obtained.
Examples of acids which may be employed to form pharmaceutically acceptable
25 acid addition salts include such inorganic acids as hydrochloric acid, sulfuric acid and
phosphoric acid and such organic acids as oxalic acid, maleic acid, methanesulfonic acid,
succinic acid and citric acid. Basic addition salts can be prepared in situ during the fmal
isolation and purification of the compounds of formula (I), or separately by reacting
carboxylic acid moieties with a suitable base such as the hydroxide, carbonate or
30 bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an
organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include,
but are not limited to, cations based on the alkali and alkaline earth metals, such as
sodium, lithium, potassium, calcimn, magnesium, aluminum salts and the Hke, as well as
wo 2005/037273
PCT/US2004/034179
nontoxic ammonium, quaternary ammonium, and amine cations, including, but not
limited to ammonitim, tetramethylammonium, tetraethylammonium, methylamine,
dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other
representative organic amines useful for the formation of base addition salts include
5 diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
As used herein, the term "pharmaceutically acceptable ester" refers to esters,
which hydrolyze in vivo and include those that break down readily in the himian body to
leave the parent compound or a salt thereof Suitable ester groups include, for example,
those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly
10 alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl
moiety advantageously has not more than 6 carbon atoms. Examples of particular esters
include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
The term "pharmaceutically acceptable prodmgs" as used herein refers to those
prodrugs of the compounds of the present invention which are, within the scope of sound
15 medical judgment, suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and the like, commensurate
with a reasonable benefit/risk ratio, and effective for their intended use, as well as the
zwitterionic forms, where possible, of the compounds of the invention. The term
"prodrug" refers to compovmds that are rapidly transformed in vivo to yield the parent
20 compoxmd of the above formula, for example by hydrolysis in blood. A thorough
discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems,
Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible
Carriers in Dmg Design, American Pharmaceutical Association and Pergamon Press,
1987, both of which are incorporated herein by reference.
25 The term "cancer" refers to cancer diseases that can be beneficially treated by the
inhibition of Raf kinase, including, for example, cancers such as malignant melanoma,
papillary thyroid cancer, cholangiocarcinoma, gallbladder carcinoma, colorectal cancer,
limg cancer, pancreatic cancer, leiikemias, prostate cancer, ovarian cancer, breast cancer
and lung cancer.
30 In illustrative embodiments of the invention, Aj may be, for example, phenyl,
phenylalkyl, pyridyl, pyrimidinyl, pyridylalkyl, pyrimidinylalkyl, alkylbenzoate,
thiophene, thiophene-2'-carboxylate, indenyl, 2,3-dihydroindenyl, tetralinyl,
trifluorophenyl, (trifluoromethyl)thiophenyl, morpholinyl, N-piperazinyl, N-
-23-
wo 2005/037273
PCT/US2004/034179
morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-
aceytl-23-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, pyrrolidinyl, pyrrolidin-
1 -yl, pyrrolidin- 1 -ylalkyl, 4-aixuno(imino)methylphenyl, isoxazolyl, indazolyl,
adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl,
phenylimidazolyl, pthalamido, napthyl, napththalenyl, benzophenone, anilinyl, anisolyl,
quinolinyl, quinolinonyl, phenylsulfonyl, phenylalkylsulfonyl, 9H-fluoren-l-yl, piperidin-
1-yl piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl, furanyl, N-methylpiperidin-4-yl,
pyrrolidin-4-ylpyridinyl, 4-dia:zepaii-l-yl, hydroxypyrrolidn-l-yl, dialkylaminopyrrolidin-
1-yl, and l,4'-bipiperidin-r-yl, which may be substituted by one or more substitutents
selected from the group consisting of hydroxyl, nitro, cyano, halo, and substituted or
imsubstituted amino, imino, thio, sulfonyl, thioamido, amidino, imidino, oxo, oxamidino,
methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, loweralkyl,
haloloweralkyl, loweralky amino, haloloweralkylamino, loweralkoxy, haloloweralkoxy,
loweralkoxyalkyl, alkylcarbonyl, aminocarbonyl, loweralkylaminocarbonyl,
heterocycloalkylloweralkylaminocarbonyl, carboxylloweralkylaminocarbonyl, aryl-
carbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio,
aminoalkyl, cyanoalkyl, aryl and the like. In other embodiments, may be substituted
phenyl, such as, for example, substituted or unsubstituted hydroxyphenyl,
hydroxyalkylphenyl, alkylphenyl, dialkylphenyl, trialkylphenyl, alkoxyphenyl,
dialkoxyphenyl, alkoxyalkylphenyl, halophenyl, dihalophenyl, haloalkylphenyl,
haloalkoxyphenyl, alkylhalophenyl, alkoxyhalophenyl, alkylthiophenyl, aminophenyl,
nitrophenyl, acetylphenyl, sulfamoylphenyl, biphenyl, alkoxybiphenyl, cyclohexylphenyl,
phenyloxyphenyl, dialkylaminophenyl, morpholinylphenyl, heterocyclylcarbonylphenyl,
heterocyclylphenyl, heterocyclylalkylphenyl, furanylphenyl, ( 1 ,4^-bipiperidin- 1
ylcarbonyl)phenyl, pyrimidin-5-ylphenyl, and quinolidinylphenyl. In yet other
embodiments, Aj is substituted phenyl selected from the group consisting of
chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, dichlorophenyl, difluorophenyl,
dibromophenyl, fluororchlorophenyl, bromochlorophenyl, trifluoromethylphenyl,
trifluoromethoxyphenyl, alkylbromophenyl, trifluoromethylbromophenyl, alkyl-
chlorophenyl, trifluoromethylchlorophenyl, alkylfluorophenyl, and trifluoromethyl-
fluorophenyl.
In representative embodiments of the invention, the compounds of the invention
include, for example, 4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}-lH-benz-
wo 2005/037273
PCT/US2004/034179
imida2ol-6-yl)oxy]-N-methylpyridine-2-carboxainide, 4-({2-[(3"Chlorophenyl)ainino]-
lH-benzimidazol-6-yl}oxy)-N-methylpyridine-2-caTboxainide, 4-({2-[(4-bromophenyl)-
amino] - 1 H-beiizimidazol-6-yl} oxy)-N-methylpyridine-2-carboxamide, 4-( {2- [(3 -chloro-
4-fluorophenyl)amino] - 1 H-benzimidazol-6-yl } oxy)-N-methylpyridine-2-carboxamide,
5 N-methyl-4- { [2-(phenylamino)- 1 H-benzimidazol-6-yl]oxy }pyridine-2-carboxamide,
4- [(2- { [4-bromo-2-(trifluoromethyl)phenyl] amino } - 1 H-benzimida2ol-6-yl)oxy] -N-
methylpyridine-2-carboxamide, N-methyl-4-({2- [(2-methylpropyl)ainino]- 1 H-benz-
imidazol-6-yl } oxy)pyridme-2-carboxamide, 4- [(2- { [4-(dimethylamino)naphthalen- 1 -yl] -
amino } - 1 H-benzimidazol-6-yl)oxy] -N-methylpyridine-2-carboxamide, N-methyl-4-( { 2-
10 [(4-mtrophenyl)amino]-lH-beiizimidazol-6-yl}oxy)pyridine-2-carboxam N-methyl-4-
( {2- [(phenylcarbonyl)axnino] - 1 H-benzimidazol-6-yl } oxy)pyridine-2-carboxamide,
methyl-4-({2-[(phenylmethyl)amino]-lH-benzimidazol-6-yl}oxy)pyridin^
amide, methyl 4-{[6-({2-[(methylamino)carbonyl]pyridin-4-yl}oxy)-lH-benzimidazol-2-
yljamino } benzoate, 4-( {2-[(4-chlorophenyl)amino] - 1 H-benzimidazol-6-yl} oxy)-N-
1 5 methylpyridine-2-carboxamide, 4-[(2- { [2-(ethyloxy)phenyl] amino } - 1 H-benzimidazol-6-
yl)oxy]-N-methylpyridine-2-carboxamide, N-methyl-4-({2-[(2-morpholin-4-ylethyl)-
amino] - 1 H-benzimidazol-6-yl } oxy)pyridine-2 -carboxamide, 4- ( { 2- [(4-iodophenyl)-
amino]-lH-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carboxamide, N-methyl-4- [(2-
{ [4-(trifluoromethyl)phenyl]amino } - 1 H-benzimidazol-6-yl)oxy]pyridine-2-carboxamide,
20 4-( { 2- [(furan-2-ylmethyl)amino] - 1 H-benzimidazol-6-yl } oxy)-N-methylpyridine-2-
catboxamide, 4-( {2- [(4-bromo-3 -methylphenyl)amino] - 1 H-benzimidazol-6-yl } oxy)-N-
methylpyridine-2-caxboxamide, 4-( {2- [(4-acetylphenyl)amino] - 1 H-benzimidazol-6-yl } -
oxy)-N-methylpyridine-2-carboxamide, N-methyl-4-({2-[(2,456-trimethylphenyl)amino]-
1 H-benzimidazol-6-yl} oxy)pyridine-2-carboxamide, 4- [(2- { [4-( 1 J -dimethylethyl)-
25 phenyl] amino } - 1 H-benzimidazol-6-yl)oxy] -N-methylpyridine-2-carboxamide, 4-( { 2- [(2-
bromophenyl)amino] - 1 H-benzimidazol-6-yl } oxy)-N-methylpyridine-2'-carboxamide5 4-
({2-[(3-bromophenyl)amino]-lH-benzimidazol-6-yl}oxy)-N-methylpyridine-2-carbox-
amide, 4-( { 2- [(2-chlorophenyl)amino] - 1 H-benzimida2ol-6-yl} oxy)-N-methylpyridine-2-
carboxamide, methyl 3- { [6-({2"[(methylamino)carbonyl]pyridin-4-yl} oxy)- 1 H-
3 0 benzimidazol-2-yl] amino }thiophene-2-carboxylate5 4-( {2- [(4-bromophenyl)amino] - 1 H-
benzimidazol-6-yl}oxy)-N-{(3R,5R)-5-[(methyloxy)methyl]pyrrolidin-3-yl}pyridine-2-
carboxamide, 4-({2-[(4-bromophenyl)amino]-l-methyl-lH-benzimida2ol-5-yl}oxy)-N-
methylpyridine-2-carboxamide5 4- [(2- { [4-chloro-3 -(trifluoromethyl)phenyl] amino } - 1 -
-25-
wo 2005/037273
PCT/US2004/034 1 79
methyl- 1 H-benzimidazol-5-yl)oxy]-N-methylpyriciine-2-carboxamide, N-methyl-4-[(l
methyl-2-{[4-(trifluoromethyl)phenyl]ainino}-lH-benzimidazol-5-yl)oxy]pyridi
carboxamide, 4-( {2- [(4-bromophenyl)amino] - 1 -methyl- 1 H-benzimidazol-5 -yl} oxy)-N-
ethylpyridine-2-carboxamide, 4-( {2-[(4-bromophenyl)ainino] - 1 -methyl- 1 H-benz-
imidazol-5-yl}oxy)-N-(2-hydroxyethyl)pyridine-2-carboxamide, 4-({2-[(4-bromo-
phenyl)amino]- 1 -methyl- 1 H-benzimidazol-5-yl> oxy)-N,N-dimethylpyridine-2-carbox-
amide, 4-( {2-[(4-bromophenyl)amino]- 1 -methyl- 1 H-benzimidazol-5-yl} oxy)-N-(2,2,2-
trifluoroethyl)pyridine-2-carboxamide, N-(4-bromophenyl)- 1 -methyl-5- { [2-(pyrrolidin- 1 -
ylcarbonyl)pyridin-4-yl] oxy } - 1 H-benzimidazol-2-amiiie, ethyl (3R)-3 -(methyloxy)-4-
[({4-[(2-{[4-(trifluoromethyi)phenyl]ammo}-lH-benzimidazol-5-yl)oxy]pyridin-2-yl}-
carbonyl)amino]piperidine-l -carboxylate, 4-({2-[(4-bromophenyl)amino]-l -methyl-lH-
benzimidazol-5-yl}oxy)-N-[2-(dimethylainino)ethyl]pyridme-2-carboxamide, 4-({2-[(4-
bromophenyl)amino]- 1 -methyl- 1 H-benzimidazol-5-yl} oxy)-N-(tetrahydrofuran-2-yl-
methyl)pyridme-2-carboxamide, 4-({2-[(4-bromophenyl)amino]-l-methyl-lH-benz-
imidazol-5-yl}oxy)-N-(2-morpholin-4-ylethyl)pyridine-2-carboxamide, 4-({2-[(4-bromo-
phenyl)amino] - 1 -methyl- 1 H-benzimidazol-S-yl} oxy)-N-(piperidin-4-ylmethyl)pyridme-
2-carboxamide, 5-({2-[(3-aminopyrrolidm-l-yl)carbonyl]pyridin-4-yl}oxy)-N-(4-
bromophenyl)- 1 -methyl- 1 H-benzimidazol-2-amine, 4-({2- [(4-bromophenyl)amino]- 1 -
methyl-lH-benzimidazol-5-yl}oxy)-N-[l-(diphenylmethyl)azetidin-3-yl]pyridine-2-
carboxamide, 4-({2-[(4-bromophenyl)amino]-l-methyl-lH-beiizimidazol-5-yl}oxy)-N-
piperidm-3-ylpyridme-2-carboxamide, 4-({2-[(4-bromophenyl)amino]-l-methyl-lH-
benzimidazol-5-yl}oxy)-N-(l ,3-thiazol-2-yl)pyridine-2-carboxamide, and 4-({2-[(4-
bromophenyl)amino]- 1 -methyl- 1 H-benzimidazol-5-yl} oxy)-N-[( 1 -ethylpyrrolidin-2-yl)-
methyl]pyridine-2-carboxamide, (4-{2-[(4-bromophenyl)ammo]benzothiazol-5-yloxy}(2-
pyridyl))-N-methylcarboxamide, (4- {2- [(4-bromophenyl)amiBo]benzoxa2ol-5-yloxy } -(2-
pyridyl))-N-methylcarboxamide, and other representative compounds set forth in the
Examples.
In other aspects, the present invention relates to the processes for preparing the
compoimds of Fonnulas (I), (II), (III), (IV), (V) and (VI) and to the synthetic
intermediates useful in such processes.
The compounds of the invention comprise asymmetrically substituted carbon
atoms. Such asymmetrically substituted carbon atoms can result in the compounds of the
invention comprising mixtures of stereoisomers at a particular asymmetrically substituted
-26-
wo 2005/037273
PCT/US2004/034179
carbon atom or a single stereoisomer. As a result, racemic mixtures, mixtures of
diastereomers, as well as single diastereomers of the compotmds of the invention are
included in the present invention. The terms "S" and "R" configuration, as used herein,
are as defined by the lUPAC 1974 Recommendations for Section E, Fundamental
Stereocpiemistry, Pure Appl Chem, 45:13-30 (1976). The terms a and p are employed
for ring positions of cyclic compounds. The a-side of the reference plane is that side on
which the preferred substituent lies at the lower numbered position. Those substituents
lying on the opposite side of the reference plane are assigned p descriptor. It should be
noted that this usage differs fi-om that for cyclic stereoparents, in which "a" means
"below the plane" and denotes absolute configuration. The terms a and p configuration,
as used herein, are as defined by the Chemical Abstracts Index Guide- Appendix IV
(1987) paragraph 203.
The present invention also relates to the processes for preparing the compounds of
the invention and to the synthetic intermediates useful in such processes, as described in
detail below.
Synthetic Methods
Compounds of the invention containing a benzimidazole core may be prepared via
a nimiber of synthetic routes using methods familiar to one of skill in the art, such as
those disclosed in WO03082272 and published U.S. Patent AppHcation No.
20040122237 Al. One such route is as shown in Scheme I below. The pyridyl ether Ig
is formed by coupling 4-halopyridine Ic with phenol If imder basic conditions. The
resulting amide Ig is treated with KOH and bromine to form the pyridyl amine Ih that
may then be coupled with various acids to form amide li. Reduction of li gives diamine
Ij, which may be coupled with various thioisocyanates to form benzimidazole Ik.
4
-27-
wo 2005/037273
PCT/US2004/034179
Scheme I
SOCI-
heat
Cf
la
lb
C!
CONH2
Ic
^sf^v^^i^v^OH HCO2H ^sN^^^rv^^OH BH3-DMS ^ 02N.,^^v,.0H
H.N-^^ AC2O ^ H-^N^^ ^ --nJ^
T« H If
K2CO3/DMF
heat
H
O2N
H
O
<^ONH2 KOH, Br2 ^ ^^^rv^^^O,^^.
H
Ig
Ih
R1COOH
BOP, DIPEA
HH
I
H
n M t=, H2/Pd/C
'^-v^'^^Y ^^^^
HN
Y ^
O
li
Ij
Ar— NCS
FeClg / MeOH
Compounds containing the oxazole structure may similarly be prepared according
to the methods above or according to other known general procedures, such as those
disclosed in WO03082272 and pubhshed U.S. Patent Application No. 20040122237 Al.
In addition, Haviv etal. (J. Med Chem. 1988, 31:1719) describes a procedure for
assembling oxazole cores wherein a hydroxy aniline is treated with ethyl potassium
xanthate. The resulting sixlfuryl benzoxazole may then be chlorinated and coupled with
an amine.
EtOCSsK
1. SOCi2
2. ArNHs
Compounds containing a benzothiazole core may also be prepared according to
known methods, such as those disclosed in WO03082272 and published U.S. Patent
Application No. 20040122237 Al. An ortho-haloamine may be reacted with a
thioisocyanate to form a thiourea. Reduction with NaH then allows formation of the
thiazole ring.
-28-
wo 2005/037273
PCT/US2004/034179
ArNCS
NaH
^NHAr
Intermediates for synthesizing benzoxazoles may generally be prepared through
the following pathway:
OoN
HO
H2/Pd/C
HoN
KOH
f EtOH, reflux 18h
EtO-^SK
SOCI2
DMF, reflux 5 min
ArNH-
DMF/NMP
48% HBr
HN
Ar
/
N
The compoimds of the invention are useful in vitro or in vivo in inhibiting the
growth of cancer cells. The compounds may be used alone or in compositions together
with a pharmaceutically acceptable carrier or excipient Suitable pharmaceutically
acceptable carriers or excipients include, for example, processing agents and drug
deUvery modifiers and enhancers, such as, for example, calcium phosphate, magnesium
stearate, talc, monosaccharides, disaccharides, starch, gelatin, ceUulose, methyl cellulose,
sodium carboxymethyl cellulose, dextrose, hydroxypropyl-P-cyclodextrin, polyvinyl-
pyrrolidinone, low melting waxes, ion exchange resins, and the like, as well as
combinations of any two or more thereof Other suitable pharmaceutically acceptable
excipients are described in "Remington's Pharmaceutical Sciences," Mack Pub. Co., New
Jersey (1991), incorporated herein by reference.
Effective amounts of the compounds of the invention generally include any
amount sufficient to detectably inhibit Raf activity by any of the assays described herein,
by other Raf kinase activity assays known to those having ordinary skill in the art or by
detecting an inhibition or alleviation of symptoms of cancer.
-29-
wo 2005/037273
PCT/US2004/034179
The amount of active ingredient that may be combined with the carrier materials
to produce a single dosage form will vary depending upon the host treated and the
particular mode of administration. It will be understood, however, that the specific dose
level for any particular patient will depend upon a variety of factors including the activity
of the specific compoimd employed, the age, body weight, general health, sex, diet, time
of administration, route of administration, rate of excretion, drug combination, and the
severity of the particular disease undergoing therapy. The therapeutically effective
amount for a given situation can be readily determined by routine experimentation and is
v^thin the skill and judgment of the ordinary clinician.
For purposes of the present invention, a therapeutically effective dose will
generally be a total daily dose administered to a host in single or divided doses may be in
amounts, for example, of from 0.001 to lOOOmg/kg body weight daily and more
preferred fi-om 1.0 to 30mg/kg body weight daily. Dosage unit compositions may
*
contain such amounts of submultiples thereof to make up the daily dose.
The compoiuids of the present invention may be administered orally, parenterally,
sublingually, by aerosolization or inhalation spray, rectally, or topically in dosage unit
formulations containing conventional nontoxic pharmaceutically acceptable carriers,
adjuvants, and vehicles as desired. Topical administration may also involve the use of
transdermal administration such as transdermal patches or ionophoresis devices. The
term parenteral as used herein includes subcutaneous injections, intravenous,
intramuscular, intrastemal injection, or infusion techniques.
Injectable preparations, for example, sterile injectable aqueous or oleaginous
suspensions may be formulated according to the known art using suitable dispersing or
wetting agents and suspending agents. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or
solvent, for example, as a solution in 1,3 -propanediol. Among the acceptable vehicles
and solvents that may be employed are water, Ringer's solution, and isotonic sodium
chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent
or suspending medium. For this purpose any bland fixed oil may be employed including
synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid find use in the
preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the
drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols,
-30-
wo 2005/037273
PCT/US2004/034179
which are solid at ordinary temperatures but Uquid at the rectal temperature and will
therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills,
powders, and granules. In such solid dosage forms, the active compoxmd may be
admixed with at least one hiert diluent such as sucrose lactose or starch. Such dosage
forms may also comprise, as is normal practice, additional substances other than inert
diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules,
tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills
can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically
acceptable emulsions, solutions, suspensions, syrups, and ehxirs containing inert diluents
commonly used in the art, such as water. Such compositions may also comprise
adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and
sweetening, flavoring, and perfuming agents.
The compoxmds of the present invention can also be administered in the form of
liposomes. As is known in the art, liposomes are generally derived from phospholipids or
other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid
crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically
acceptable and metaboUzable lipid capable of forming liposomes can be used. The
present compositions in liposome form can contain, in addition to a compoxmd of the
present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids
are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed.,
Methods in Cell Biology, Volume XIV, Academic Press, New York, N.W., p. 33 et seq.
(1976).
While the compounds of the invention can be administered as the sole active
pharmaceutical agent, they can also be used in combination with one or more other agents
used in the treatment of cancer. Representative agents useful in combination with the
compounds of the invention for the treatment of cancer include, for example, irinotecan,
topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes,
tezacitabine, cyclophosphamide, vinca alkaloids, imatinib (Gleevec), anthracyclines,
rituximab, trastuzximab, as well as other cancer chemotherapeutic agents.
-31-
wo 2005/037273
PCT/US2004/034179
The above compounds to be employed in combination with the compounds of the
invention will be used in therapeutic amounts as indicated in the Physicians^ Desk
Reference (PDR) 47th Edition (1993), which is incorporated herein by reference, or such
therapeutically useful amounts as would be known to one of ordinary skill in the art.
5 The compounds of the invention and the other anticancer agents can be
administered at the recommended maximum clinical dosage or at lower doses. Dosage
levels of the active compounds in the compositions of the invention may be varied so as
to obtain a desired therapeutic response depending on the route of administration, severity
of the disease and the response of the patient. The combination can be administered as
10 separate compositions or as a single dosage form containing both agents. When
administered as a combination, the therapeutic agents can be formulated as separate
compositions, which are given at the same time or different times, or the therapeutic
agents, can be given as a single composition.
Antiestrogens, such as tamoxifen, inhibit breast cancer growth through induction
15 of cell cycle arrest, that requires the action of the cell cycle inhibitor p27Kip. Recently, it
has been shown that activation of the Ras-Raf-MAP Kinase pathway alters the
phosphorylation status of p27Kip such that its inhibitory activity in arresting the cell
cycle is attenuated, thereby contributing to antiestrogen resistance (Donovan et al, J. Biol.
Chem, 27^:40888, 2001). As reported by Donovan et al., inhibition of MARK signaling
20 through treatment with MEK inhibitor changed the phosphorylation status of p27 in
hormone refactory breast cancer cell lines and in so doing restored hormone sensitivity.
Accordingly, in one aspect, the compoimds of formulas (I), (II), (III), (IV) and (V) may
be used in the treatment of hormone dependent cancers, such as breast and prostate
cancers, to reverse hormone resistance commonly seen in these cancers with conventional
25 anticancer agents.
In hematological cancers, such as chronic myelogenous leukemia (CML),
chromosomal translocation is responsible for the constitutively activated BCR-ABl
tyrosine kinase. The afflicted patients are responsive to Gleevec, a small molecule
tyrosine kinase inhibitor, as a result of inhibition of Abl kinase activity. However, many
30 patients with advanced stage disease respond to Gleevec initially, but then relapse later
due to resistance-conferring mutations in the Abl kinase domain. In viti^o studies have
demonstrated that BCR-Avl employs the Raf kinase pathway to elicit its effects. In
addition, inhibiting more than one kinase in the same pathway provides additional
-32-
wo 2005/037273
PCT/US2004/034179
protection against resistance-conferring mutations. Accordingly, in another aspect of the
invention, the compomds of formulas (I), (11), (III), (IV) and (V) are used in combination
with at least one additional agent, such as Gleevec, in the treatment of hematological
cancers, such as chronic myelogenous leukemia (CML), to reverse or prevent resistance
5 to the at least one additional agent.
The present invention will be understood more readily by reference to the
following examples, which are provided by way of illustration and are not intended to be
limiting of the present invention.
Representative side chains for use in the compounds of the following examples
10 may generally be prepared in accordance with the following procedures:
Example 1
Synthesis of N- [4-( ( 2- [(3 -tert-butvbhenvDaminol - 1 -methvl- 1 H-
benzimidazol-5 -yl } oxy)pyridin-2"yl] acetamide
/
15 Stepl:
2. NaNg, water, 0 ''C
1a
3. f-BuOH, toluene, 100 °C
Triethylamine (5 mL, 35.6 mmol) was added to a stirring suspension of acid la
(3.34 g, 1 1.6 mmol) in dry THF (44 mL) at 0 ""C. The reaction was maintained at 0 ""C for
1 h, after which a solution of /^obutylchloroformate (1.8 mL, 13.9 mmol) in dry THF (14
20 mL) was added dropwise. After 1 h at 0 a solution of sodium azide (2.28 g, 35.1
mmol) in water (8 mL) was added and the resulting reaction was maintained at 0 °C for
-33-
wo 2005/037273
PCT/US2004/034179
10
15
45 min. The reaction solution was concentrated into an aqueous slxirry and partitioned
between saturated aqueous NaHCOs solution and CH2CI2. The phases were separated
and the aqueous portion was extracted with CH2CI2 (3 X). The combined organics were
washed with brine and the combined aqueous portions were further extracted with
CH2CI2. The combined organic phases were dried (MgS04) and concentrated to give
2.71 g (8.6 mmol, 75%) of an orange solid as crude acyl azide.
A suspension of acyl azide (322 mg, 1.02 mol) and ^-butanol (0.2 mL, 2.09 mmol)
in dry toluene (12 mL) was heated to 100 °C and maintained at that temperature for 1 .5 h.
The reaction was allowed to cool to rt and then partitioned between saturated aqueous
Na2C03 solution and CH2CI2. The phases were separated and the aqueous portion was
extracted with CH2CI2 (3 X). The combined organic portions were washed with saturated
aqueous Na2C03 solution (2 X) and brine, dried (MgS04)5 and adsorbed onto Si02.
Purification by flash chromatography (9:1,4:1,2:1 hexanes-EtO Ac) afforded 131 mg
(0.36 mmol, 36%) of an orange solid as lb: NMR (300 MHz, CDCI3) 5 8.18 (br s, 1
H), 8.12 (d, J= 5.8 Hz, 1 H), 8.04 ( br dd, 1 H), 7.95 (d, 2.8 Hz, 1 H), 7.53 (d, J= 2.2,
1 H), 7.29 (dd, J- 2.8, 9.1 Hz, 1 H), 6.91 (d, J- 9.3 Hz, 1 H), 6.47 (dd, 2.5, 5.8 Hz, 1
H), 3.07 (d, J- 5.2 Hz, 3 H), 1.49 (s, 9 H).
Step 2:
MeHN
TFA, CH2CI2
MeHN
1b
1c
20 Trifluoroacetic acid (4 mL) was added to a stirring suspension of BOC carbamate
lb (181 mg, 0.5 mmol) in CH2CI2 (4 mL). The resulting reaction was maintained at rt for
3.5 h and was then concentrated. The crude residue was suspended in saturated aqueous
Na2C03 and extracted with CH2CI2 (3 X). The combined organic portions were
concentrated and the resulting residue was adsorbed onto Si02. Purification by flash
25 chromatography (0.5 : 99.5, 0.75 : 99.25, 1 : 99, 2 : 98, 5 : 95 methanol-CH2Cl2) gave 94
mg (0.36 mmol, 72%) of a bright orange soUd as Ic: ^H NMR (300 MHz, CDCI3) 5 8.03
(br d, /= 3.3 Hz, 1 H), 7.93 (d, J= 2.8 Hz, 1 H), 7.92 (d, J= 5.8 Hz, 1 H), 7.27 (dd, J =
-34-
wo 2005/037273
PCT/US2004/034179
2.8, 9.4 Hz, 1 H), 6.89 (d, 9.3 Hz, 1 H), 6.24 (dd, 2.2, 6.0 Hz, 1 H), 5.92 (d, J
2.2 Hz, 1 H), 4.44 (br s, 2 H), 3.05 (d, J= 5.0 Hz, 3 H).
Step 3 :
AC2O, pyridine
1
dioxane, 85 °C
1c
1d
5 Pyridine (0.08 mL, 0.99 mmol) and acetic anhydride (0.04 mL, 0,42 mmol) was
added to suspension of 2-am.inopyridine Ic (94 mg, 0.36 mmol) in dry dioxane (1.7 nxL).
The resulting reaction mixture was heated to and maintained at 85 for 2 h. The
reaction was allowed to cool to rt and was then partitioned between EtOAc and saturated
aqueous Na^COs. The layers were separated and the aqueous layer was extracted with
10 EtOAc (3 X). The combined organic portions were washed with brine, dried (MgS04),
and adsorbed onto Si02. Purification by flash chromatography (2:1, 1:1, 1:2, 1:3
hexanes-EtOAc) provided 75 mg (0.25 mmol, 69 %) of an orange solid as Id: ^H NMR
(300 MHz, CDCI3) 5 8.35 (br s, 1 H), 8.10 (d, J= 5.8 Hz, 1 H), 8.05 (br d, J= 4.4 Hz, 1
H), 7.95 (d, J= 2.8 Hz, 1 H), 7.76 (br d, J- 1.7 Hz 1 H), 7.30 (dd, J= 2.7, 9.1 Hz, 1 H),
15 6.91 (d, J- 9.3 Hz, 1 H), 6.60 (dd, J= 2.5, 5.8 Hz, 1 H), 3.05 (d, J= 5.2 Hz, 3 H), 2.16
(s, 3 H).
Step 4:
H
1d
1. 10% Pd/C, H2. MeOH
, MeOH
NCS
3. FeCIs, pyridine
1e
A suspension of acetamide Id (75 mg, 0.25 mmol) aad 10% Pd/C (30 mg, 0.03
20 mmol) in methanol (5 mL) was charged with H2 and the resulting reaction mixture was
maintained under a H2 atmosphere for 1 h at rt. The mixture was filtered and the
-35-
wo 2005/037273
PCT/US2004/034179
remaining solids washed thoroughly with EtOAc and methanol. The combined organic
portions were evaporated to afford 60 mg (0.22 mmol, 88%) of a brown residue as the
phenylene diamine, which was carried forward without further purification.
The above diamine (60 mg, 0.22 mmol) was dissolved in methanol (3 mL) and a
5 solution of 3-^^r^-butyl phenylthioisocyanate (62 mg, 0.32mmol) in methanol was added.
The reaction was maintained for 16 h. Pyridine (0.06 mL, 0.74 mmol) was added to the
reaction, followed by ferric chloride (45 mg, 0,28 mmol). The resulting dark reaction
mixture was maintained at rt for 16 h, then suspended in saturated aqueous Na2C03
solution, and filtered with Celite. The remaining solids were washed with EtOAc and the
10 combined filtrate was partitioned and separated. The aqueous portion was extracted with
EtOAc (3 X) and the combined organic portions were washed with brine, dried (MgS04),
and evaporated. Purification by semi-prep HPLC gave le as the TFA salt which was
neutralized with saturated aqueous Na2C03 solution and extracted with EtOAc (3 X).
The combined organic portions were washed with brine and water, dried (MgS04), and
1 5 evaporated. The resulting residue was reconstituted as the mono citrate salt: LCMS m/z
430.3 (MH^), /r = 2.24 min.
Example 2
Synthesis of N'[4-( (2-[(4-fluoro-3 -tetrahvdrofuran-3 - vlphenvDaminol- 1 -methyl- 1 H-
ben2:imidazol-5-yl>oxy)pyridin-2-yl]acetamide
20 '
Synthesized as described above in Example 1 using 3-(2-fluoro-5-isothiocyanato-
phenyl)-tetrahydro-furan. LCMS m/z 462.2 (MH^), 2.51 min.
-36-
wo 2005/037273
PCT/US2004/034179
Example 3
Synthesis of N-r4- 1 [ 1 -methyl-2-( f 4- ["( trifluoromethvDthiol phenyl > aminoV 1 H-
ben2imidazol-5"yl]oxy>pyridin"2-yl'>acetaxnide
/
5 Synthesized as described above in Example 1 using 4-trifluoromethylthiophenyl
isothiocyanate. LCMS m/z (MR% 3.41 min.
Example 4
Synthesis of N- \A-( 1 2- ["(4-fluorQ-3 ■isopropylphenyDamino] - 1 -methyl- 1 H-benzimidazol-
5-yU oxy)pyridin-2"yl]acetamide
Synthesized as described above in Example 1 using 4-fluoro-3-isopropylphenyl
isothiocyanate. LCMS m/z 434.2 (MH^), 3.28 min.
-37-
wo 2005/037273
PCT/US2004/034179
Example 5
Synthesis of N- ( 4-rr2" I r4-fIuQro-3 -(3 -furvDphenvn amino ) - 1 -metJiyl- 1 H-benzimidazol-
5 - vDoxvlp Yridin-2- vl \ acetamide
/
Synthesized as described above in Example 1 using 3-(2-fluoro-5-isothiocyanato-
phenyl)-fLiran. LCMS m/z 458.3 (MH^), 2.02 min.
Example 6
Synthesis of N-[4--( f 2-[(4-jB[uoro-3 "tetrahydrofLiran-2-ylphenyDamino1 - 1 -methyl- 1 H-
benzimidazol-5-yU oxy)pyridin-2-yn acetamide
Synthesized as described above in Example 1 using 2-(2-Fluoro-5-isothiocyanato-
phenyl)-tetrahydro-furan. LCMS m/z 462.3 (MET"), R, 1.87 min.
Example 7
Synthesis of N- [4-( 1 2- r(4-chloro-3 -i sopropylphenvDamino] - 1 -methyl- 1 H-benzimi dazol-
5-yUoxy)pyridin-2-yl"|-l-methylpiperidine-4-carboxamide
-38-
wo 2005/037273
PCT/US2004/034179
1 . Synthesis of [(4-(2-amino(4-pyridyloxy))-2-iiitrophenyl]methylamine
Bromine (1.3eq) was added dropwise to a solution of potassium hydroxide (lOeq)
at -10°C. 4-(4-methylamino-3-nitrophenoxy)-pyridine-2-carboxamide (leq) was added
followed by dioxane and the mixture was heated to SO^'C for one hour. The mixture was
5 then cooled to ambient temperature followed by slow addition of acetic acid (5eq). The
solution was heated to eO^'C for one hour. The solution was brought to pH=8 with acetic
acid. [4-(2-amino(4-pyridyloxy))-2-nitrophenyl]methylamine precipitated as an orange
solid on cooling which was collected by filtration and washed with water and dried. MS :
1^11^=261.
10 2. Synthesis of l-methyl-A^-(4-{[4-(methylamino)-3-nitrophenyl]oxy}pyridin-2-yl)-
piperidine-4-carboxamide
To a mixture of l-methylpiperidine-4-carboxylic acid (leq) in N,N-dimethyl
formamide and N,N-disopropylethylamine (4eq) was added BOP (2eq) and the mixture
was stirred at ambient temperature until homogeneous. To it was added [4-(2-amino(4-
15 pyridyloxy))-2-nitrophenyl]methylamine (leq) and the resulting mixture was stirred at
60°C for 16h. The reaction mixture was then concentrated and partitioned between ethyl
acetate and water. The organic layer was dried over sodium sulfate and the resulting 1-
xnethy l-iV^-(4- { [4-(methylamino)-3 -nitrophenyl] oxy } pyridin-2 -yl)piperidine-4-
carboxamide was purified by silica gel chromatography. MS: MET^ = 386.2.
20 3. Synthesis of N-(4-{[3-amino-4-(methylamino)phenyl]oxy}pyridin-2'-yl)-l-
methylpiperidine-4-carboxamide
The mixture containing l-methyl-A^-(4-{[4-(methylamino)-3-nitrophenyl]oxy}-
pyridin-2-yl)piperidine-4-carboxamide in methanol with catalytic amoxmt of Lindlar's
catalyst was hydrogenated to yield iV-(4-{[3-amino-4-(methylamino)phenyl]oxy}pyridin-
25 2-yl)-l-methylpiperidine-4-carboxamide. MS: MH"*" =356.2.
4. Synthesis of N-[4-({2-[(4-chloro-3-isopropylphenyl)amino]-l-methyl-lH-
benzimidazol-5-yl}oxy)pyridin-2-yl]- 1 -methylpiperidine-4-carboxamide
To 4-chloro-3-(methylethyl)ben2eneisothiocyanate (leq) in methanol was added
7V-(4- { [3 -amino-4-(methylamino)phenyl] oxy } pyridin-2-yl)- 1 -methylpiperidine-4-carbox-
30 amide (leq) and the resulting mixture was stirred at ambient temperature for 16h.
LC/MS showed formation of the corresponding thiourea. To it in methanol was then
-39-
wo 2005/037273
PCT/US2004/034179
added anhydrous ferric chloride (1.5eq) and stirred for 3h. The reaction mixture was then
concentrated to half its volume and brought to basic pH with saturated sodium carbonate
solution. The aqueous solution was filtered through celite and was then extracted with
ethyl acetate and the organic layer was washed with brine and dried with sodium sulfate.
5 The crude was then triturated with hot ether with a few drops of ethyl acetate to yield N-
N- [4-({2- [(4-chloro-3 -isopropylphenyl)amino] - 1 -methyl- 1 H-benzimidazol-5-
yl}oxy)pyridin-2-yl]-l-methylpiperidine-4-carboxamide. MS: MH'^^ 534. L
Example 8
Synthesis of l-ethyl-N-(4-r(2-(r2-fluoro-5-(trifluoromethyl)phenyl"[amino>-l-methyl-
10 lH-benzimidazol-5-yl)oxy]pyridin-2-yl)piperidine-4-carbQxamide
1 . Synthesis of l-(ethyl)piperidine-4-carboxylic acid
To ethylpiperidine-4-carboxylate (leq) in ethanol was added iodoethane (1.1 eq)
and potassiimi carbonate (2eq) and the resulting mixture was refluxed for 16h. The
1 5 mixture was then cooled to room temperature and filtered. Ethanol was concentrated and
partitioned between methylene chloride and water. The organic layer was then washed
with saturated sodium chloride solution, dried with sodium sulfate and concentrated. To
it was then added concentrated hydrochloric acid and water (2:1) and the mixture was
refluxed for 5h. The resulting 1 -(ethyl)piperidine-4-carboxylic acid was then azeotroped
20 with toluene. MS: MH^ - 158.
2. Synthesis of ((l-ethyl)(4-piperidyl))-N-{4-{4-(methylamino)-3-nitrophenoxy}(2-
pyridyl) } carboxamide
To a mixture of 1 -(ethyl)piperidine-4-carboxylic acid (leq) in N^N-dimethyl
formamide and N^N-disopropylethylamine (4eq) was added BOP (2eq) and the mixture
25 was stirred at ambient temperature until homogeneous. To it was added [4-(2-amino(4-
pyridyloxy))-2-nitrophenyl]methylamine (leq) and the resulting mixture was stirred at
for 1 6h. The reaction mixture was then concentrated and partitioned between ethyl
acetate and water. The organic layer was dried over sodiimi sulfate and the resulting ((1-
/
-40-
wo 2005/037273
PCT/US2004/034179
ethyl)(4-piperidyl))-N-{444-(methylamino)-3-iutrophenoxy]}
was purified by silica gel chromatography. MS: IVfltf" = 400.2.
3. Synthesis of N-[4-{3-amino-4-(niethylamino)}phenoxy](2-pyridyl)-(l-ethyl(4-
piperidyl))carboxainide
The mixture containing (( 1 -ethyl) (4-piperidyl))-N- {4- [4-(methylamino)-3 -
nitrophenoxy]}(2-pyridyl))carboxamide in methanol with catalytic amount of Lindlar's
catalyst was hydrogenated to yield N-[4-{3-amino-4-(methylamino)}phenoxy](2-
pyridyl)-(l-ethyl(4-piperidyl))carboxamide. MS: MH^ =370.2.
4. Synthesis of l-ethyl-N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-l-methyl-
lH-benzimidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide
To 2-fluoro-5-(trifluoromethyl)ben2:eneisothiocyanate (leq) in methanol was
added N-[4-{3-amino-4-(methylamino)}phenoxy](2-pyridyl)-(l-ethyl(4-piperidyl))-
carboxamide (leq) and the resulting mixture was stirred at ambient temperature for 16h.
LC/MS showed formation of the corresponding thiourea. To this in methanol was then
added anhydrous ferric chloride (1 .5eq) and stirred for 3h. The reaction mixture was then
concentrated to half its volume and brought to basic pH with saturated sodium carbonate
solution. The aqueous solution was filtered through celite and was then extracted with
ethyl acetate and the organic layer was washed with brine and dried with sodiiim sulfate.
The crude was then triturated with hot ether with a few drops of ethyl acetate to yield 1-
ethyl-N- {4- [(2- { [2-fluoro-5-(trifluoromefhyl)phenyl] amino } - 1 -methyl- 1 H-benzimidazol-
5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide. MS: MH"*" = 557.6,
Example 9
Synthesis of N-f4-[(2-ir2-fluoro-5-rtrifluoromethynr>henynamino>-l-methvl-lH-
benzimidazol-5-ynQxy1pyridin-2-yU-l-isoprop yl piperidine"4-carboxamide
-41-
wo 2005/037273
PCT/US2004/034179
1 . Synthesis of 1 -(methylethyl)piperidine-4-carboxylic acid
To ethylpiperidine-4-carboxylate (leq) in methanol was added acetone (Icq) and
acetic acid (5%) and the resulting mixture was stirred for 2h at ambient temperature. To
it was then added sodium cyanoborohydride (leq) and continued stirring for 16h. The
5 mixture was then concentrated and to it was added sodium bicarbonate and was
partitioned between ethyl acetate and water. The organic layer was dried with sodium
sulfate and concentrated to yield ethyl- l-(metliyletliyl)piperidine ^-carboxylate. To this
was then added concentrated hydrochloric acid and water (2:1) and the mixture was
refluxed for 5h. The resulting l-(methylethyl)piperidine-4-carboxylic acid was then
10 azeotroped with toluene. MS: MH^ =172.
2. Synthesis of N- {4- [4-(methylamino)3 -nitrophenoxy] (2-pyridyl) } - [ 1 -(methylethyl)(4-
piperidyl] carboxamide
To a mixture of 1 -(methylethyl)piperidine-4-carboxylic acid (leq) in N,N-
dimethyl foimamide and N,N-disopropylethylamine (4eq) was added BOP (2eq) and the
1 5 mixture was stirred at ambient temperature until homogeneous. To it was added [4-(2-
amino(4-pyridyloxy))-2-mtrophenyl]methylamine (leq) and the resulting mixture was
stirred at 60°C for 16h. The reaction mixture was then concentrated and partitioned
between ethyl acetate and water. The organic layer was dried over sodium sulfate and the
resulting N-{4-[4-(methylamino)3-nitrophenoxy](2-pyridyl)}-[l-(methylethyl)(4-
20 piperidyl]caxboxamide was purified by silica gel chromatography. MS: MH"^ =414.2.
3 . Synthesis of N- {4- [3 -amino-4-(methylamino)phenoxy] (2-pyridyl) } - [ 1 -methylethyl)(4-
piperidyl)]carboxamide
The mixture containing N-{4-[4-(methylamino)3-nitrophenoxy](2-pyridyl)}-[l-
(methylethyl)(4-piperidyl] carboxamide in methanol with catalytic amount of Lindlar's
25 catalyst was hydrogenated to yield N-{4-[3-amino-4-(methylamino)phenoxy](2-
pyridyl)}-[l-(methylethyl)(4-piperidyl)]carboxamide. MS: MH"^ =384.2.
4. Synthesis of N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-l-methyl-lH-
benzimidazol-5-yl)oxy]pyridin-2-yl} - 1 -isopropylpiperidine-4-carboxamide
To 2-fluoro-5-(trifluoromethyl)benzeneisothiocyanate (leq) in methanol was
3 0 added N- {4- [3 -amino-4-(methylamino)phenoxy] (2-pyridyl) } - [ 1 -(methylethyl)(4-
piperidyl)] carboxamide (leq) and the resulting mixture was stirred at ambient
-42-
wo 2005/037273
PCT/US2004/034179
temperature for 1 6h. LC/MS showed formation of the corresponding thiourea. To it in
methanol was then added anhydrous ferric chloride (1.5eq) and stirred for 3h. The
reaction mixture was then concentrated to half its volume and brought to basic pH with
saturated sodium carbonate solution. The aqueous solution was filtered through celite
5 and was then extracted with ethyl acetate and the organic layer was washed with brine
and dried with sodiiom sulfate. The crude was then triturated with hot ether with a few
drops of ethyl acetate to yield N'{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-l-
methyl- lH-benzimidazol-5 -yl)oxy]pyridin-2-yl} - 1 -isopropylpiperidine-4-carboxamide,
MS: MH^ = 571.6.
10 Example 10
Synthesis of N- 1 4- 1"(2- ( r2-fluoro-5 -rtrifluoromethyDphenvll amino > - 1 -methyl- 1 H-
benzimidazo 1- 5 -yl')oxylpyridin-2-y 1 1 - 1 -(2 -methoxYethYl')piperidine-4-carboxamide
1 . Synthesis of 1 '-(2-methoxyethyl)piperidine-4-carboxylic acid
15 To ethylpiperidine-4-carboxylate (leq) in ethanol was added 2-bromo-l-
methoxyethane (leq) and potassium carbonate 2eq) and the resulting mixture was
refluxed for 16h. The mixture was then filtered and concentrated. To it was then added
ethanol and water (3:1) and sodiixm hydroxide (leq) and it was refluxed for 16h. The
resulting l-(2-methoxyethyl)piperidine-4-carboxylic acid was then azeotroped with
20 toluene. MS: MH^ = 188.
2. Synthesis of [l-(2-methoxyethyl)(4-piperidyl)}-N-{4-[4-(methylamino)-3-
nitrophenoxy] (2- [pyridyl) } carboxamide
To a mixture of l-(2-methoxyethyl)piperidine-4-carboxylic (leq) in N^N-dimethyl
formamide and N,N-disopropylethylamine (4eq) was added BOP (2eq) and the mixture
25 was stirred at ambient temperature until homogeneous. To it was added [4-(2-amino(4-
pyridyloxy))-2-nitrophenyl]methylamine (leq) and the resulting mixture was stirred at
-43-
wo 2005/037273
PCT/US2004/034179
60^C for 16h. The reaction mixture was then concentrated and partitioned between ethyl
acetate and water. The organic layer was dried over sodium sulfate and the resulting [1-
(2-methoxyethyl)(4-piperidyl) } -N- {4- [4-(methylamino)-3 -nitrophenoxy] (2- [pyridyl) } -
carboxamide was purified by silica gel chromatography. MS: MBT^ = 430.2.
3. Synthesis of N-{4[3-amino-4-(methylamino)phenoxy](2-pyridyl)}[l-(2-
methoxyethyl)(4-piperidyl)] carboxamide
The mixture containing [ 1 -(2-methoxyethyl)(4-piperidyl) } -N- {4- [4-(methyl-
amino)-3-nitrophenoxy](2-[pyridyl)}carboxamide in methanol with catalytic amoxmt of
Lindlar's catalyst was hydrogenated to yield N-{4[3-amino-4-(methylamino)phenoxy](2-
pyridyl)}[l-(2-methoxyethyl)(4-piperidyl)] carboxamide. MS: MHT^ -400.2.
4. Synthesis of N- {4-[(2- { [2-fluoro-5-(trifluoromethyl)phenyl]amino } - 1 -methyl- 1 H-
benzimidazol-5-yl)oxy]pyridin-2-yl}-l-(2-methoxyethyl)piperidine-4-carboxamide
To 2-fluoro-5-(trifluoromethyl)benzeneisothiocyanate (leq) in methanol was
added N-{4[3-amino-4-(methylamino)phenoxy](2-pyridyl)}[l-(2-methoxyethyl)(4-
piperidyl)] carboxamide (leq) and the resulting mixture was stirred at ambient
temperature for 1 6h. LC/MS showed formation of the corresponding thiourea. To it in
methanol was then added anhydrous ferric chloride (1.5eq) and stirred for 3h. The
reaction mixture was then concentrated to half its volume and brought to basic pH with
saturated sodium carbonate solution. The aqueous solution was filtered through elite and
was then extracted with ethyl acetate and the organic layer was washed with brine and
dried with sodium sulfate. The crude was then triturated with hot ether with a few drops
of ethyl acetate to yield N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-l-methyl-
lH-benzimidazol-5-yl)oxy]pyridin-2-yl}-l-(2'-methoxyethyl)piperidine-4-carboxamide.
MS: MH^= 587.6.
-44-
wo 2005/037273
PCT/US2004/034179
Example 11
Synthesis of N-(4-[(2-ir2-fluQrQ-5-ftrifluoromethyl)phenvl]aminol"l-met^^
beiiziinidazol-5 -yPoxy] pyridin-2"yl> - 1 -(2-hydroxyet3iyDpiperidine-4-carboxami de
F
5 To N- { 4- [(2- { [2-fluoro-5 -(trifluoromethyl)phenyl] amino} - 1 -methyl- 1 H-benz-
imidazol-5-yl)oxy]pyridin-2-yl } - 1 -(2-methoxyethyl)piperidine-4-carboxamide ( 1 eq) in
methylene chloride at — 78*^0 was added IM borontribromide in methylene chloride
(lOeq) and the resulting mixture and the resulting mixture was stirred at -78°C for Ih. It
was then brought to ambient temperature and stirred for 2h. LC/MS showed formation of
1 0 the product. The reaction was quenched with saturated sodium carbonate solution at 0*^C.
The mixture was concentrated and tlien brought to pH=9. It was then extracted with ethyl
acetate and the organic layer was dried with soditim sulfate and concentrated and purified
on preparative chromatography to yield N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)-
phenyl] amino } - 1 -methyl- 1 H-benzimidazol-5-yl)oxy]pyridin-2-yl} - 1 -(2-hydroxyethyl)-
15 piperidine-4-carboxamide. MS: MH^ = 573.6.
Example 12
Synthesis ofN-(4-[(2-( |'2-fluoro - 5 -ftrifluoromethyDphenyll amino > - 1 -methyl- 1 H-
benzimidazol-5-yl)oxy1pyridin-2-yl } piperidine"4-carboxamide
F
-45-
wo 2005/037273
PCT/US2004/034179
1. Synthesis of tert-butyl-4-(N-{4-[4-(methylammo)-3-nitroph^ pyridyl}
carbamoyl)piperidinecarboxylate
To a mixture of l-(tert-butoxy)carbonylpiperidine-4-carboxylic acid (leq) in N^N-
dimethyl formamide and N,N-disopropylethylamine (4eq) was added BOP (2ec[) and the
5 mixture was stirred at ambient temperature until homogeneous. To it was added [4-(2-
amino(4-pyridyloxy))-2-nitrophenyl]methylamine (leq) and the resulting mixture was
stirred at 60*^0 for 16h. The reaction mixture was then concentrated and partitioned
between ethyl acetate and water. The organic layer was dried over sodium sulfate and the
resulting tert-butyl-4-(N-{4-[4-(methylamino)-3-nitrophenoxy]-2- pyridyl} carbamoyl)
10 piperidinecarboxylate was purified by silica gel chromatography. MS: MIT^ = 472.2.
2. Synthesis of tert-butyl-4-(N-{4-[3-amino-4-(methylamino)phenoxy]-2-pyridyl-
carbamoyl) piperidinecarboxylate
The mixture containing tert-butyl-4-(N-{4-[4-(methylamino)-3-nitrophenoxy]-2-
P3a:idyl} carbamoyl) piperidinecarboxylate in methanol with catalytic amount of Lindlar^s
15 catalyst was hydrogenated to yield tert-butyl-4-(N-{4-[3-amino-4-(methylamino)-
phenoxy]-2-p3aridylcarbamoyl) piperidinecarboxylate. MS: MH^ = 442.2.
3 . Synthesis ofN-{4-[(2-{ [2 -fluoro-5 -(trifluoromethyl)phenyl] amino } - 1 -methyl- 1 H-
ben2imidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide
To 2-fluoro-5-(trifluoromethyl)benzeneisothiocyanate (leq) in methanol was
20 added tert-butyl-4-(N-{4-[3-amino-4-(methylamino)phenoxy]-2-pyridylcarbamoyl) piper-
idinecarboxylate (leq) and the resulting mixture was stirred at ambient temperature for
1 6h. LC/MS showed formation of the corresponding thiourea. To it in methanol was
then added anhydrous ferric chloride (1.5eq) and stirred for 3h. The reaction mixture was
then concentrated to half its volume and brought to basic pH with saturated sodium
25 carbonate solution. The aqueous solution was filtered through celite and was then
extracted with ethyl acetate and the organic layer was washed with brine and dried with
sodium sulfate. The crude was then triturated with hot ether with a few drops of ethyl
acetate to yield the product. To it in methylene chloride was then added trifluoroacetic
acid to yield N- { 4- [(2 - { [2-fluoro -5 -(trifluoromethyl)phenylj amino } - 1 -methyl- 1 H-
30 benzimidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide. MS: MH"^ = 529.5.
-46-
wo 2005/037273
PCT/US2004/034179
Example 13
Synthesis of 1 -acetvl-N- 14- \(2' I [2-fluoro--5-( trifluorometfayDphenyll amino > - 1 -methyl-
1 H-benzimidazol-S -vl)oxv]pvri din-2"Vl I piperi dine-4-carboxatnide
F
/
5 To N- {4- [(2- { [2-fluoro-5 -(trifluoromethy l)phenyl] amino } - 1 -methyl- 1 H-benz-
imidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide (leq) in dioxane and N,N-
disopropylethylamine (2eq) was added acetic anhydride (leq) and the resulting mixture
was stirred for 1 h. 1 -acetyl-N- {4-[(2- { [2-fluoro-5-(trifluoromethyl)phenyl]amino} - 1 -
met±Lyl- 1 H-benzimidazol-5-yl)oxy]pyridin-2-yl } piperidine-4-carboxamide thus formed
10 was purified by preparative chromatography. MS: MH^ = 571.5.
Example 14
Synthesis of N- (4- [(2- 1 r2-fluoro-5"(trifluoromethynphenyl1 amino 1-1 -methyl- 1 H-
benzimidazol-5 -yl)oxy]pyridin-2-yl > -3 -piperidin-4-ylpropanatnide
15 1. Synthesis of tert-butyl-4-[2-(N-{4-{4-(methylamino)-3-nitrophenoxy]-2-
pyridylcarbamoyl)ethyl] piperidinecarboxylate
To a mixture of 3 -{l-[(tert-butyl)oxycarbonyl]-4-piperidyl} propanoic acid (leq)
in N-,lS[-dimethyl formamide and N^N-disopropylethylamine (4eq) was added BOP (2eq)
and the mixture was stirred at ambient temperature until homogeneous. To it was added
20 [4-(2-amino(4-pyridyloxy))-2-nitrophenyl]methylamine (leq) and the resulting mixture
was stirred at 60°C for 1 6h. The reaction mixture was then concentrated and partitioned
-47-
wo 2005/037273
PCT/US2004/034179
between ethyl acetate and water. The organic layer was dried over sodimn sulfate and the
resulting tert-butyl-4-[2-(N-{4-{4-(methylamino)-3-rdtrophenoxy]-2-pyridylcarbara
ethyl] piperidinecarboxylate was purified by silica gel chromatography. MS: MH^ =
500.2.
5 2. Synthesis of tert-butyl-4-[2-(N-{4-[3-amino-4-(methylamino)phenoxy]-2-
P3T:idyl}carbamoyl)ethyl] piperidine carboxylate
The mixture containing tert-butyl-4-[2-(N-{4-{4-(methylamino)-3-mtrophenoxy]-
2-pyridylcarbamoyl)ethyl] piperidinecarboxylate in methanol with catalytic amount of
Lindlar's catalyst was hydrogenated to yield tert-butyl-4-[2-(N-{4-[3-amino-4-
10 (methylamino)phenoxy]-2-pyridyl}carbamoyl)ethyl] piperidine carboxylate. MS: M¥t
= 470.2.
3 . Synthesis of N- [4'-(2- { [2-fluoro-5 -(trifluoromethyl)phenyl] amino- 1 -methylbenz-
imidazol-5 -yloxy)(2-pyridyl] -3 -(4-piperidyl)propanamide
To 2-fluoro-5-(trifluoromethyl)ben2eneisothiocyanate (leq) in methanol was
15 added tert-butyl-4-[2-(N-{4-[3-amino-4-(methylamino)phenoxy]-2-pyridyl}carbamoyl)"
ethyl] piperidine carboxylate (leq) and the resulting mixture was stirred at ambient
temperature for 1 6h. LC/MS showed formation of the corresponding thiourea. To it in
methanol was then added anhydrous ferric chloride (1.5eq) and stirred for 3h. The
reaction mixture was then concentrated to half its volume and brought to basic pH with
20 saturated sodium carbonate solution. The aqueous solution was filtered through celite
and was then extracted with ethyl acetate and the organic layer was washed with brine
and dried with sodium sulfate. The crude was then triturated with hot ether with a few
drops of ethyl acetate to yield the product. To it was then added trifluoroacetic acid to
yield N- {4- [(2- { [2-fluoro-5-(trifluoromethyl)phenyl] amino } - 1 -methyl- 1 H-benzimidazol-
25 5-yl)oxy]pyridin-2-yl}-3-piperidin-4-ylpropanamide. MS: MH"^ = 557.6.
-48-
wo 2005/037273
PCT/US2004/034179
Example 15
Synthesis of N- (4- [(2- ( [2-fluoro-5-rtrifluorQmethyl')phenyl1ammo > - 1 -methyl" 1 H-
benzimidazol-5-yl')oxy1pyridin"2-yl > -3 -( 1 -methylpiperidm-4-yl)propanamide
F
/
TTo N- {4- [(2- { [2-fluoro- 5-(trifluoromethyl)phenyl] amino } - 1 -methyl- 1 H-benz-
imidazol-5-yl)oxy]pyridin-2-yl}-3-piperidin-4-ylpropanamide (leq) in methanol was
added formalin (2eq) and acetic acid(5%) foUovsred by sodium cyanoborohydride (2eq)
and the resulting mixture was stirred at ambient temperature for 3h. LC/MS showed
formation of the product. The crude mixture was then concentrated and to it was added
sodium bicarbonate and the resulting mixture was partitioned between ethyl acetate and
water. The organic layer was dried with sodium sulfate and purified by preparative
chromatography to yield N- {4-[(2- { [2-fluoro-5-(trifluoromethyl)phenyl] amino } - 1 -
methyl-lH-benzimidazol-5-yl)oxy]pyridin-2-yl}-3-(l-methylpiperidin-4-yl)propanamide.
MS: MHT- 571.6.
Example 16
Synthesis of N- 14-['(2- ( r2-fluorQ-5-( trifluoromethynphenyllaminol - 1 -methyl- 1 H-
ben:zimidazol-5 -yl)oxy1pyridin-2-yl 1 -3 -H -isopropylpiperidin-4-yl)propanamide
-49-
wo 2005/037273
PCT/US2004/034179
1. Synthesis of N-[4-(2-{ [2-fluoro-5-trifluoromethyl)phenyl] amino)- 1-
metiiylbenzimidazol-5 -yloxy)(2-pyridyl)] -3 - [ 1 -(methylethyl)(4-piperidyl)]propanamide
To N- [4-(2 - { [2 -fluoro-5 -(trifluoromethyl)phenyl] amino - 1 -methylbenzimidazol-S -
yloxy)(2-pyridyl]-3-(4-piperidyl)propanamide (leq) in methanol was added acetone (2eq)
and acetic acid(5%) followed by sodium cyanoborohydride (2eq) and the resulting
mixture was stirred at ambient temperature for 3h. LC/MS shows formation of the
product. The crude mixture was then concentrated and to it was added sodium
bicarbonate and the resulting mixture was partitioned between ethyl acetate and water.
The organic layer was dried with sodixmi sulfate and purified by preparative
chromatography to yield N-{4-[(2- { [2-fluoro-5-(trifluoromethyl)phenyl]amino} - 1 -
methyl- 1 H-benzimidazol-5-yl)oxy]pyridin-2-yl} -3 -(1 -isopropylpiperidin-4-
yl)propanamide. MS: MET*' = 599.6.
Example 17
Synthesis of N- 1 — ( 4 - ["(2- 1 r2-fluoro-5 -CtrifluoromethyDphenyll amino > - 1 -methyl- 1 H-
benzimidazol- 5 -yl)oxy] pyridin-2-yl ) -N-2 — methyl glycinamide
F
1 . Synthesis of 2-[(tert-butoxy)-N-methylcarbonylamino]-N-{4-[4-(methylamino)-3-
nitrophenoxy] (2-pyridyl)acetamide
To a mixture of 2- [(tert-butoxy)-N-methylcarbonylamino] acetic acid (leq) in
N^N-dimethyl formamide and N^N-disopropylethylamine (4eq) was added BOP (2eq) and
the mixture was stirred at ambient temperature until homogeneous. To it was added [4-
(2-amino(4-pyridyloxy))-2-nitrophenyl]methylamine (leq) and the resulting mixture was
stirred at 60°C for 16h. The reaction mixture was then concentrated and partitioned
between ethyl acetate and water. The organic layer was dried over sodium sulfate and the
resulting 2-[(tert-butoxy)-N-methylcarbonylamino]-N-{4-[4-(methylamino)-3-nitrophen-
oxy] (2-pyridyl)acetamide was purified by silica gel chromatography. MS: MH^ = 432.2.
-50-
wo 2005/037273
PCT/US2004/034179
2. Synthesis of N-{4-[3-amino-4<methylamino)phenoxy](2-pyridyl)}-2-[(te^^^
N-methylcarbonylamino] acetamide
The mixture containing 2-[(tert-butoxy)-N-methylcarbonylatnino]-N- {4-[4-
(methylaraino)-3-nitrophenoxy](2-pyridyl)acetamide in methanol with catalytic amount
5 of Lindlar's catalyst was hydrogenated to N-{4-[3-amino-4-(methylamino)phenoxy](2-
pyridyl)}-2-[(tert-bntoxy)-N-methylcarbonylamino]acetamide. MS: MH^ =402.2.
3 . Synthesis of N-1 — {4-[(2- { [2-fluoro-5-(trifluoromethyl)phenyl]amino } - 1 -methyl- IH-
benzimidazol-5-yl)oxy]pyridin-2-yl}-N-2'— methylglycinamide
To 2-fluoro-5-(trifluoromethyl)benzeneisothiocyanate (leq) in methanol was
1 0 added N- { 4- [3 -amino-4-(methylamino)phenoxy] (2-pyridyl) } -2- [(tert-butoxy)-N-methyl-
carbonylam^ino] acetamide (leq) and the resulting mixture was stirred at ambient
temperature for 1 6h. LC/MS showed formation of the corresponding thiourea. To it in
methanol was then added anhydrous ferric cliloride (1.5eq) and stirred for 3h. The
reaction mixture was then concentrated to half its volume and brought to basic pH with
15 saturated sodium carbonate solution. The aqueous solution was filtered through celite
and was then extracted with ethyl acetate and the organic layer was washed with brine
and dried with sodium sulfate. The crude was then triturated with hot ether with a few
drops of ethyl acetate to yield the product. To it in methylene chloride was then added
trifluoroacetic acid to yield N~l—{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-l-
20 methyl-lE[-benzimidazol-5-yl)oxy]pyridin-2-yl}-N-2---methylglycinamide. MS: MH^ ==
489.4.
Example 18
Synthesis of N- ( 4- \(2- ( ["2-fluoro -5 -(trifluoromethvl)phenyll amino > - 1 -methyl- 1 H-
benzimidazol- 5 -yl)oxy1 pyridin-2-yl } -4-morpholin-4-ylbutanamide
-51-
wo 2005/037273
PCT/US2004/034179
1. Synthesis of N-{4-[4-(methylamino)-3-nitrophenoxy](2-pyridyl)}-4-mo^^
ylbutanamide
To a mixture of 4-morpholino-4-yibutanoic acid (Icq) in N^N-dimethyl
formamide and N,N-disopropylethylamine (4eq) was added BOP (2eq) and the mixture
5 was stirred at ambient temperature imtil homogeneous. To it was added [4-(2-amino(4-
pyridyloxy))-2-nitrophenyl]methylamine (leq) and the resuhing mixture was stirred at
eO'^C for 1 6h. The reaction mixture was then concentrated and partitioned between ethyl
acetate and water. The organic layer was dried over sodium sulfate and the resulting N-
{4-[4-(metlaylamino)-3-nitrophenoxy](2--pyridyl)}-4-morpholino-4-ylbutanamide was
10 purified by silica gel chromatography. MS: MH^ = 416.2.
2. Synthesis of N-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl))-4-morpholin-4-
ylbutanamide
The mixture containing N-{4-[4-(methylainino)-3-nitrophenoxy](2-pyridyl)}-4-
morpholinD-4-ylbutanamide in methanol with catalytic amount of Lindlar's catalyst was
15 hydrogenated to yield N-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl))-4-
morpholin-4-ylbutanamide. MS: MH"^ ^386.2.
3 . Synthesis of N- {4-[(2- { [2-fluoro-5-(trifluoromethyl)phenyl]amino} - 1 -methyl- 1 H-
benzimidazol-5-yl)oxy]pyridin-2-yl}-4-morpholin-4-ylbutanamide
To 2-fluoro-5-(trifluoromethyl)benzeneisothiocyanate (leq) in methanol was
20 added N-{4-[3-amino-4--(methylamino)phenoxy](2-pyridyl))-4-morpholin-4-ylbutan-
amide (leq) and the resulting mixture was stirred at ambient temperature for 16h.
LC/MS showed formation of the corresponding thiourea. To it in methanol was then
added anhydrous ferric chloride (1.5eq) and stirred for 3h. The reaction mixture was then
concentrated, to half its volrmie and brought to basic pH with saturated sodium carbonate
25 solution. The aqueous solution was filtered through celite and was then extracted with
ethyl acetate and the organic layer was washed with brine and dried with sodimn sulfate.
The crude was then triturated with hot ether with a few drops of ethyl acetate to N-{4-[(2-
{ [2-fluoro-5 -(trifluor omethyl)phenyl] amino } - 1 -methyl- 1 H-benzimidazol-S -yl)oxy] -
pyridin-2-yl>-4-morpholin-4-ylbutanamide. MS: Mlt = 573.6.
-52-
wo 2005/037273
PCT/US2004/034179
Example 19
Synthesis of N- 1 4- 1(2- i r2-fluoro-5-rtrifluoromethvl)phenYn amino I - 1 -methyl- 1 H-
benzimidazol-5-vnoxvlpYridin--2-vlV2-r4-(2-methoxyethvnpiperaz in"l-yl1acetamide
F
5 1 . Synthesis of 2- [4-(2-methoxyethyl)piperizinyl] -N- (4- [4-(methylamino-3 -
nitrophenoxy] (2-pyridyl) } acetamide
To 2-chloro-N-{4-[4-(methylamino)-3-nitrophenoxy](2-pyridyl)}acetamide (leq)
in acetonitrile was added 1 -methoxy-2-piperizinylethane (leq) and potassiimi carbonate
(2eq) and the resulting mixture was heated to 60*^0 for 16h. It was then concentrated and
10 partitioned between ethyl acetate and water. The organic layer was dried with sodiiun
sulfate and concentrated to give 2-[4-(2-methoxyethyl)piperizinyl]-N-{4-[4-(methyl-
amino-3-nitrophenoxy](2-pyridyl)}acetamide. MS: MH"^ = 445.2.
2. Synthesis of N-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-2-[4-(2-
methoxy ethyl) piperizinyl] acetamide
15 The mixture containing 2-[4-(2-methoxyethyl)piperizinyl]-N-{4-[4"(methyl-
amino-3 -nitrophenoxy] (2-pyridyl)} acetamide in methanol with catalytic amount of
Lindlar's catalyst was hydrogenated to yield N-{4-[3-amino-4-(methylamino)phenoxy](2-
pyridyl)}-2-[4-(2-methoxyethyl)piperizinyl]acetamide. MS: MET^ =415.2.
3 . Synthesis of N-{4-[(2- { [2-fluoro-5-(trifluoromethyl)phenyl]amino} - 1 -methyl- IH-
20 benzimidaz;ol-5-yl)oxy]pyridin-2-yl}-2-[4-(2-methoxyethyl)piperazin-l-yl]acetamide
To 2-fluoro-5-(trifluoromethyl)benzeneisothiocyanate (leq) in methanol was
added N- {4- [3 -amino-4-(niethylamino)phenoxy] (2-pyridyl) } -2- [4-(2-methoxyethyl)-
piperizinyl] acetamide (leq) and the resulting mixture was stirred at ambient temperature
for 1 6h. LC/MS showed formation of the corresponding thiourea. To it in methanol was
25 then added anhydrous ferric chloride (L5eq) and stirred for 3h. The reaction mixture was
then concentrated to half its volume and brought to basic pH with saturated sodium
-53-
wo 2005/037273
PCT/US2004/034179
carbonate solution. The aqueous solution was filtered through celite and was then
extracted with ethyl acetate and the organic layer was washed with brine and dried with
sodium sulfate. Tlie crude was then triturated with hot ether with a few drops of ethyl
acetate to yield N- {4- [(2- { [2-fluoro-5-(trifluoromethyl)phenyl] amino } - 1 -methyl- 1 H-
ben2imidazol-5-yl)oxy]pyridin-2-yl}-2-[4-(2-methoxyethyl)piperazin-l-yl]acetamide.
MS: MH^ = 602.6.
Example 20
Synthesis of N- 1 4~ \(2- ( r2-fluoro-5-r trifluoromethyDnhenvll amino > - 1 -methyl- 1 H-
bellzimi dazol-5-^^noxy1pyridin-2-yU-2-^4-(^2-hydroxyethyDpiperazin-l-yl^acetalnide
F
To N- { 4- [(2- { [2-fluoro-5 -(trifluoromethyl)phenyl] amino } - 1 -methyl- 1 H-benz-
imidazol-5-yl)oxy]pyridin-2-yl}-2-[4-(2-methoxyethyl)piperazin-l-yl]acetamide (leq) in
methylene chloride at -78*^C was added IM borontribromide in methylene chloride
(lOeq) and the resulting mixture was stirred at -TS'^C for Ih. It was then brought to
ambient temperature and stirred for 2h. LC/MS showed formation of the product. The
reaction was quenctied with saturated sodium carbonate solution at 0°C. The mixture was
concentrated and tiien brought to pH=9. It was then extracted with ethyl acetate and the
organic layer was dried with sodium sulfate and concentrated and purified on preparative
chromatography to yield N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-l-
methyl-lH-benzimidazol-5-yl)oxy]pyridin-2-yl}-2-[4-(2-hydroxyethyl)piperazin-l-yl]-
acetamide. MS: MH"^ = 588,6.
-54-
wo 2005/037273
PCT/US2004/034179
Example 21
Synthesis of N-(4- i r2"r4-chlorobenzYlV 1 -methyl- lH-benzimidazol"5-vl]oxvlpYridm-2--
yDacetamide
/
5 To N-{4-[3-amino-4-(methylamino)phenoxy]}-2-pyridylacetamide (leq) in tetra-
hydrofuran added EDC (2eq) and HO AT (leq) and N,N-disopropylethylamine (4eq) and
2-(4-chloropherLyl)acetic acid (leq) and the resulting mixture was stirred at ambient
temperature for 1 6h. The reaction mixture was then partitioned between ethyl acetate and
water. The organic layer was then dried with sodium sulfate and concentrated to give N-
1 0 {4-[2-(acetylamino)(4-pyridyloxy)]-2-aminophenyl} -2-(4-chlorophenyl)-N-methyl-
acetamide. To it was added acetic acid and the resulting mixture was heated to 60°C for
4h. The cmde was purified by preparative chromatography to give N-(4-{[2-(4-
chlorobenzyl)-! -methyl- lH-benzimidazol-5-yl]oxy}pyridin-2-yl)acetamide. MS: MH^ =
407.9.
15 Example 22
Synthesis of N- f 4-( { 2- [(4-chlQrophenyl)amino1 - 1 -methyl- 1 H-benzimidazol-5 -
yl I oxy')pyridin-2-yl]benzamide
/
To [5-(2-amino(4-pyridyloxy))- 1 -methylbenzimidazol-2-yl] (4-chlorophenyl)-
20 amine (leq) in tetrahydrofurari added EDC (2eq) and HO AT (leq) and N,N-
disopropylethylamine (4eq) and benzoic acid (leq) and the resulting mixture was stirred
at ambient temperature for 1 6h. The reaction mixture was then partitioned between ethyl
-55-
wo 2005/037273
PCT/US2004/034179
acetate and water. The organic layer was then dried with sodium sulfate and concentrated
and purified by preparative chromatography to to give N-[4-({2-[(4-chloro-
phenyl)amino]- 1 -methyl- 1 H-benzimidazol-5-yl} oxy)pyridin-2-yl]benzamide. MS : MH"^
= 470.9.
Example 23
Synthesis of N-r4"ri 2- rn-tert-butylphenvDaminol-l -methyl- IH-benzimidazol-S-
vl ) oxy)pyridin-2-yn -N^-f 2-morpholin-4-ylethyl)urea
3. FeCIs
Step 1: Synthesis of N-{4-[4-(methylamino)-3-nitrophenoxy](2-pyridyl)}[(2-morpholin-
4-ylethyl)amino]carboxamide
A flame dried flask was charged with 4-[4-(methylamino)-3-nitrophenoxy]-
pyridine-2-carboxylic acid (leq), diphenylphosphoryl azide (l.leq), triethylamine (2.1eq)
and 20 ml toluene and heated for one and one half hours at VS^'C. To this was added 2-
morpholin-4-ylethylaiiiine (1.2eq) and the resulting mixture was stirred at IS^'C
overnight. The reaction was then concentrated and partitioned between ethyl acetate and
distilled water. The organic layer was dried with sodium sulfate and concentrated and
titurated with ether then hexanes to give the purified product. MS: MH^ = 417.
Step 2: Synthesis of N-{4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}[(2-
morpholin-4-ylethyl)amino] carboxamide
To a flask containing N-{4-[4-(methylamino)-3-nLtrophenoxy](2-pyridyl)}[(2-
morpholin-4"-ylethyl)amino] carboxamide in methanol was added a catalytic amoimt of
10% Pd/C and hydrogenated to yield in quantitative amount N-{4-[3-amino-4-
(methylamino)phenoxy](2-pyridyl)}[(2-morpholin-4-ylethyl)amino]carboxamide.MS:
MH"' = 387.
-56-
wo 2005/037273
PCT/US2004/034179
Step 3: Synthesis of 3-Ctert-butyl)benzenisothiocyanate
To 3-(tert-butyl)phenylamine in acetone at O^C was added sodiiom bicarbonate
(2eq) and thiophosgene (2eq). The mixture was brought to ambient temperature and
concentrated and partitioned between ethyl acetate and water. The organic layer was
dried with sodium bicarbonate and sodium sulfate and concentrated to yield 3-(tert-
butyl)benzenisothiocyai:iate. MS: MH"^ =192.
Step 4: Synthesis of N-[4-({2-[(3-tert-butylphenyl)amino]-l-methyl-lH-benzimidazol-5-
yl } oxy)pyridin-2-yl] -N' - (2-morpholui-4-ylethyl)urea
To 3-(tert-butyl)benzenisotliiocyanate (leq) in methanol was added N-{4-[3-
amino-4-(methylamino)phenoxy] (2-pyridyl) } [(2-morpholin-4-ylethyl)amino]carbox-
amide (leq) and the resulting mixture was stirred at ambient temperature for 16h.
LC/MS showed formation of corresponding thiourea. To this was added anhydrous ferric
chloride (1.5eq) and stirred for 3h. The reaction mixture was then concentrated to half its
volume and brought to neutral pH with IN soditun hydroxide. It was then extracted with
ethyl acetate and the organic layer was washed with brine and dried with sodium sulfate.
The crude material was then purified on preparative chromatography to yield N-[4-({2-
[(34ert-butylphenyl)amino]-l-methyl-lH-benzimidazol-5-yl}oxy)pyridin-2-yl]-N'-(2-
morpholin-4-ylethyl)urea. MS: MH"^ = 544.
Example 24
Synthesis of 2'( 4-ethvlpiperazin- 1 -ylVN- 1 4- \(2~ ( r2-fluoro-5-
(trifluoromethyDphenyll amino > - 1 -methyl- 1 H-benzimidazol-5 ■ynoxvlpyridin-2-
vUacetamide
1 . Synthesis of N-(4-(4<methylamino)-3-nitrophenoxy)pyridin-2-yl)-2-chloroacetamide
A solution of 4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-amine (leq) and
triethylamine (2 eq) in tetrahydrofuran was treated with 2-chloroacetyl chloride and
-57-
wo 2005/037273
PCT/US2004/034179
stirred for 1 5 minutes at room temperature. The reaction mixture was then concentrated
and partitioned between ethyl acetate and water. The organic layer was separated and
washed with brine, dried over sodium sulfate and concentrated in vacuum to give crude
product. Purification on silica gel with 2% methanol in methylene chloride gave N-(4"-(4-
5 (methylamino)-3-nitrophenoxy)pyridin-2-yl)-2-chloroacetamide as a bright orange solid.
HPLC = 3.82min; MS: MH" = 337.
2. Synthesis of N-(4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-yl)-2-(4-
ethylpiperazin- 1 -yl)acetamide
The mixture containing N-(4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-yl)-2-
10 chloroacetamide (leq), 1 -ethylpiperazine (3eq), and potassium carbonate (4eq) was
stirred in dimethylformamide at 60^C for 1 hour. The reaction mixture was then
concentrated and partitioned between ethyl acetate and water. The organic layer was
separated and washed with water then brine, dried over sodiiom sulfate and concentrated
to give orange solid. Purification on silica gel with 20% methanol in methylene chloride
1 5 gave N-(4-(4-(methylamino)-3 -nitrophenoxy)pyridin-2-yl)-2-(4-ethylpiperazin- 1 -yl)-
acetamide as a red solid. HPLC = 3.26min; MS: MHr'-415.
3. Synthesis of N-(4-(3-amino-4-(methylamino)phenoxy)pyridin-2-yl)-2-(4-
ethylpiperazin- 1 -yl)acetamide
The mixture containing N-(4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-yl)-2'-
20 (4-ethylpiperazin-l-yl)acetamide in methanol with a catalytic amotmt of 10% Pd/C
poisoned with lead was hydrogenated until the disappearance of the yellow color. The
reaction was then filtered to remove the catalyst and concentrated to yield N-(4-(3-amino-
4-(methylamino)phenoxy)pyridin-2-yl)-2-(4-ethylpiperazin- 1 -yl)acetamide as a brown
oil, HPLC = 2,00 min; MS: MH^-385.
25 4. Synthesis of 2-(4-ethylpiperazin-l-yl)-N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]-
amino } - 1 -methyl- 1 H-benzimidazol-5-yl)oxy]pyridin-2-yl } acetamide
A solution of N-(4-(3-amino-4-(methylamino)phenoxy)pyridin-2-yl)-2-(4-ethyl-
piperazin-l-yl)acetamide (leq) in methanol was treated with l-fluoro-4-(trifluoromethyl)-
2-isothiocyanatobenzene (leq) and stirred at room temperature for 16 hours to form the
30 corresponding tliiourea. To it was then added iron (III) chloride (1.2eq) and stirred for
another 4 hours. The mixture was then concentrated and partitioned between saturated
-58-
wo 2005/037273
PCT/US2004/034179
sodium carbonate and ethyl acetate. The organic layer was separated and washed with
water and brine, dried over sodium sulfate and concentrated to give brown crude solid.
Purification by trituration with 5% ethyl acetate in diethyl ether to give 2-(4-
ethy Ipiper aziu- 1 -yl)-N- { 4- [(2 - { [2-fluoro - 5 -(trifluoromethyl)phenyl] amino } - 1 -methyl-
5 lH-benzimidazol-5-yl)oxy]pyridin-2-yl}acetamide as tan solid. HPLC = 3.40min; MS;
Mtt = 572.
Example 25
Synthesis of N- 1 4- \(2-{ r4-chJoro-3 -(3 "fluoropyridin-4-yl)phenyn amino VI -methyl- 1 H-
benzimidazol"5 -yPoxylpyri din-2-yl > acetamide
1. Synthesis of 4-(2-chloro-5-nitrophenyl)-3-fluorop5T:idine
A mixture of DME: H20 (3:1) was degassed with N2 for one half hour. 2-bromo-
1 -chloro-4-nitrobenzene (leq) added and degassed for another 10 minutes. 1,1'-
bis(diphenylphosphino)ferrocene palladium(II)chloride (0.05eq), 3-fluoropyridin-4-yl-4-
15 boronic acid (leq), and sodimrx carbonate (3eq) were then added and stirred at lOO^C for
16 hours. Reaction then concentrated and partitioned between ethyl acetate and water.
Organic layer washed with brine, dried over sodixrai sulfate and concentrated.
Purification on silica gel, 10% ethyl acetate in hexanes to yield 4-(2-chloro-5"
nitrophenyl)-3-fluoropyridine. HPLC = 4.57min; MS: MI^" = 253.
20 2, Synthesis of 4-chloro-3-(3-flluoropyridin-4-yl)benzenamine
4-(2-chloro-5-nitrophenyl)-3-fluoropyridine (leq) was stirred with Iron (0), (3eq),
in acetic acid for 10 hours at room temperature. Reaction neutralized with sodium
carbonate and filtered to remove iron. Reaction partitioned between ethyl acetate and
water. Organic layer separated and washed with brine, dried over sodium sulfate and
25 concentrated to give 4-chloro-3-(3-fluoropyridin-4-yl)benzenamine. HPLC = 1.72min;
MS: MH^ = 223.
N
10
-59-
wo 2005/037273
PCT/US2004/034179
3. Synthesis of 4-(2-chloro-5-isothiocyanatophenyl)-3-fluoropyridme
The mixture containing 4-chloro-3-(3-fluoropyridin-4-yl)benz;enamine (leq) and
sodium bicarbonate (2eq) in acetone was treated with thiophosgene (2eq) and stirred for 5
minutes at O^'C. Reaction then concentrated and partitioned between ethyl acetate and
5 water. Organic layer dried over sodium sulfate and sodium bicarbonate and concentrated
to give 4-(2-chloro-5-isothiocyanatophenyl)-3-fluoropyridine. HPLC = 5.54min; MS:
MH^-265.
4. Synthesis of N- {4- [(2- { [4-chloro-3 -(3 -fluoropyridin-4-yl)phenyl] amino } - 1 -methyl-
1 H-benzimidazol-5 -yl)oxy]pyridin-2-yl } acetamide
10 The mixture containing 4-(2-chloro-5-isothiocyanatophenyl)-3-fluoropyridine
(leq) and N-(4-(3-amino-4-(methylamino)phenoxy)pyridin-2-yl)acetamide (leq) in
methanol was stirred at room temperature of 16 ho\H*s to give the corresponding thiourea.
To it was then added iron (III) chloride (1.2eq) and stirred for another 4 hours. The
mixture was then concentrated and partitioned between saturated sodium carbonate and
15 ethyl acetate. The organic layer was separated and washed with water and brine, dried
over sodium sulfate and concentrated to give brown crude solid. Purification on HPLC to
yield N- { 4-[(2- { [4-chloro-3 -(3 -fluoropyridin-4-yl)phenyl] amino } - 1 -methyl- 1 H-benz-
imidazol-5-yl)oxy]pyridin-2-yl}acetamide. HPLC = 3.37min; MS: MH^ - 503
Example 26
20 Synthesis of N-r4-f (2-rG-isoDropvlphenvnaminQl-L3"benzothiazol-5-yl>oxy)pvridin-2-
yl] acetamide
1. Synthesis of N-(3-isopropylphenyl)-5-methoxybenzo[d]tliiazol-2-amine
The mixture containing 2-bromo-5-methoxybenzo[d]thiazole (leq), 3-
25 isopropylbnezylamine (1.5eq) and diisopropylethylamine (4eq) was subjected to
microwave in NMP at 235*^C for 15 minutes. Reaction partitioned between ethyl acetate
-60-
wo 2005/037273
PCT/US2004/034179
and water. Organic layer separated and washed with brine, dried over sodium sulfate and
concentrated. Purification on silica gel, 10% ethyl acetate in hexane to give N-CS-
isopropylphenyl)-5-methoxybenzofd]thiazol-2-ainine. HPLC = 5.50min; MS: MHT" -
299.
5 2, Synthesis of 2-(3-isopropylpherLylaniino)benzo[d]thiazol-5-ol
N-(3-isopropylphenyl)-5-methoxybenzo[d]thiazol-2-amine was charged with
hydrobromic acid (45%) and subjected to microwave at 170°C for 10 minutes. Reaction
was then neutralized with sodium carbonate (saturated solution) and partitioned between
ethyl acetate and water. The organic layer was separated, washed with brine, dried over
10 sodiimi sulfate and concentrated to give 2-(3-isopropylphenylamino)benzo[d]thiazol-5-oL
HPLC - 4.63min; MS: MH^ = 285 .
3 . Synthesis of N- [4-( { 2- [(3 -isopropylpheny l)amino] - 1 ,3 -benzothiazol-5 -yl} oxy)pyridin-
2-yl]acetamide
The mixture containing 2-(3-isopropylphenylamino)benzo[d]thiazol-5-ol (leq),
15 N-(4-chloropyridin-2-yl)acetamide (1.4eq), potassium bis(trimethylsilyl)amide (4eq) and
potassium carbonate (1.2eq) in diraethylformamide was subjected to the microwave at
200^C for 15 minutes. The reaction was then partitioned between ethyl acetate and water.
The organic layer was separated, washed with brine, dried over soditim sulfate and
concentrated to give the crude product. Purification on HPLC to yield N-[4-({2-[(3-
20 isopropylphenyl)amino]-l ,3-ben2otl:iiazol-5-yl}oxy)pyridin-2-yl]acetamide. HPLC =
4.87min;MS: MH^ = 419.
Example 27
Synthesis of N- [4-( ( 2- [(3 -tert-butvlphenvDamino] - 13 -benzothiazol- 5 - vl I oxv^p vridin-2'-
vl]- 1 ■meth'vlpiperidine-4-carboxamide
-61-
wo 2005/037273
PCT/US2004/034179
1 . Synthesis of 1 -methylpiperidine-4-carbonyl chloride
A flask was flame dried and placed under a nitrogen atmosphere. 1-
methylpiperidine-4-carboxylic acid (leq) in anhydrous methylene chloride added to flask
and cooled to 20°C in a water bath. Dimethylformamide added, then oxalyl chloride
5 (1.4eq) in methylene chloride. Reaction refluxed for 2 hours, brought to room
temperature, concentrated and azeotroped with toluene to yield 1 -methylpiperidine-4-
carbonyl chloride as a light yellow fluffy solid. MS: MH^ =162.
2. Synthesis of N-(4-chloropyridin-2-yl)-l-methylpiperidine-4-carboxamide
A flask was flame dried and placed under a nitrogen atmosphere. 1-
10 methylpiperidine-4-carbonyl chloride (leq) in anhydrous methylene chloride was added
to the flask and brought to 0°C. To this was added the solution containing 4-
chloropyridin-2-amine (leq), and diisopropylethylamine (5eq) in anhydrous methylene
chloride, which was stirred for 1 hoxor at O^C. Reaction concentrated and partitioned
between water and ethyl acetate. The organic layer was separated, washed with brine,
15 dried over sodium sulfate and concentrated to give the crude product. Purification on
silica gel, 10% metlianol in methylene chloride to yield N-(4-chloropyridin-2-yl)-l-
methylpiperidine-4-carboxamide as a slightly yellow crystal solid. HPLC = 2.39min;
MS: MH^-254.
3 . Synthesis of N- [4-( {2- [(3 -tert-bixtylphenyl)amino] -1,3 -benzothiazol-5 -yl } oxy)pyridin-
20 2-yl] - 1 -methylpiperidine-4-carboxarQide
The mixture containing 2-(3-tert-butylphenylamino)benzo[d]thiazol-5-ol (leq),
potassium bis(trimethylsilyl)amide (4eq), and potassium carbonate (1.2eq) in
dimethylformamide was stirred at room temperature for 1 0 minutes, N-(4-chloropyridin-
2-yl)-l-methylpiperidine-4-carboxaraide (1.4eq) was then added and mixture subjected to
25 microwave at 220°C for 20 minutes. Reaction partitioned between ethyl acetate and
water. Organic layer separated, washed with brine, dried over sodium sulfate and
concentrated to give crude product. Purification by HPLC to yield N-[4-({2-[(3-tert-
butylphenyl)amino]- 1 ,3 -benzothiazol-5 -yl } oxy)pyridin-2-yl] - 1 -methylpiperidine-4-
carboxamide. HPLC = 4.74min; MS: MH^ = 516.
-62-
wo 2005/037273
PCT/US2004/034179
Example 28
Synthesis of N-(44(2-(r2-fluoro-5-rtrijauoromethvnphenvl1amm^
lH-ben2iraidazQl-5-vDoxv1pyridin-2"vl)acetainide
5 1. Synthesis of 4-(2-methoxy-4-(methylamino)-5-mtrophenoxy)pyridine-2-carboxylic
acid
Trifluoroacetic acid was added neat to tert-butyl 4'-(2-methoxy-4-(methylainino)-
5-nitrophenoxy)pyridine-2-carboxylate and stirred at room temperatixre for 5 hours. TFA
was evaporated, solid product azeotroped with toluene then placed under vacuum for 24
1 0 hours to yield 4-(2-methoxy-4-(methylamino)-5 -nitrophenoxy)pyridine-2-carboxylic
acid. HPLC-3.07min;MS: MH''-321
2. Synthesis of 4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridine-2-carboxamide
The mixture containing 4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridine-
2-carboxylic acid (leq), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2eq), 3H-1,2,3-
15 triazolo[4,5-b]pyridine-3-ol (1.5eq), and diisopropylamine (5eq) in tetrahydrofuraa was
stirred at room temperature for Ihour. To this was then added ammonium chloride (2eq)
and the resulting mixture was stirred together for 48 hours. Reaction concentrated.
Purification on silica gel, 50% acetone in hexanes to yield 4-(2-methoxy-4-
(methylamino)-5-nitrophenoxy)pyridine-2-carboxamide as a bright yellow solid. HPLC
20 =3.70min;MS: MH^-319.
3. Synthesis of 4-(2-methoxy-4-(metliylamino)-5-nitrophenoxy)pyridin-2-amine
Liquid bromine (2eq) was added dropwise to a solution of potassium hydroxide
(lOeq) in water at O^C. 4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridine-2-
carboxamide (leq) was then added in a small amoxmt of dioxane. Reaction brought to
25 room temperature for hour then heated to 55°C for 1 hour showing a red homogenous
"63-
wo 2005/037273
PCT/US2004/034179
solution. The reaction was brought back to 0°C and acetic acid (excess) was added. The
mixture was heated at SS^'C for hoor, cooled to room temperature and sodium
carbonate added to neutralize. Reaction wras extracted with methylene chloride. Organic
layer washed with brine, dried over soditmi sulfate and concentrated to yield 4-(2-
methoxy-4-(methylamino)-5-nitrophenoxy)pyridin-2-amine as an orange soUd. HPLC
3.10min;MS: MH^ = 292.
4. Synthesis of N-(4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridin-2-
yl)acetamide
Under a nitrogen atmosphere, 4-(2"methoxy-4-(methylamino)-5-nitrophenoxy)-
pyridin-2 -amine (leq) and diisopropylethylamine (4eq) in methylene chloride was
brought to O^'C. Acetyl chloride (l.leq) -was added dropwise and mixture stirred for 5
minutes. Reaction brought to room temperatwe and water added. Organic layer washed
with brine, dried over sodixrai sulfate ajad concentrated to yield N-(4-(2-methoxy-4-
(methylamino)-5-nitrophenoxy)pyridin-2-yl)acetamide. HPLC = 3.21min; MS: MH^ =
^3 ^5 ^5 ■*
5. Synthesis of N-(4-(5-amino-2-methoxy-4-(methylamino)phenoxy)pyridin-2-
yl)acetamide
The mixture containing N-(4^(2-methoxy-4-(methylamino)-5-nitrophenoxy)-
pyridin-2-yl)acetamide in methanol with a catalytic amouuit of 10% Pd/C poisoned with
lead was hydrogenated until the disappearance of the yellow color. The reaction was
then filtered to remove the catalyst and concentrated to yield N-(4-(5-amino-2-methoxy-
4-(methylamino)phenoxy)pyridin-2-yl)acetamide. HPLC = 2.25min; MS: MH''-=303.
6. Synthesis of N- {4- [(2- { [2-fluoro-5-(trifluoromethyl)phenyl]amino } -6-methoxy- 1 -
methyl- lH-benzimidazol-5-yl)oxy]pyridirx-2-yl} acetamide
A solution of N-(4-(5-amino-2"methoxy-4-(methylamino)phenoxy)pyridin-2-
yl)acetamide (leq) in methanol was treated with l-fluoro-4-(trifluoromethyl)-2-
isothiocyanatobenzene (leq) and stirred at room temperature for 16 hours to form the
corresponding thiourea. To it was then added iron (III) chloride (1.2eq) and stirred for
another 4 hours. The mixture was then concentrated and partitioned between saturated
sodiimi carbonate and ethyl acetate. The organic layer was separated and washed with
water and brine, dried over sodium sulfate and concentrated to give brown crude solid.
-64-
wo 2005/037273
PCT/US2004/034179
Purification by HPLC to yield N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-6-
methoxy-1 -methyl- lH-benzimida2ol-5-yl)oxy]pyridin-2-yl}acetamide HPLC = 3.02min;
MS: MH''-490.
Example 29
5 Synthesis of N- r4-f -f 2- [(3 -isopropylphenvDaminol - 1 -methyl- 1 H-benzimidazol- 5 -
yl I oxy)pyridin.-2-yl] -2-piperidin-4-ylacetamide
1. Synthesis of 5-(2-aminopyTidin-4-yloxy)-N-(3-isopropylphenyl)-l -methyl- IH-
benzo [d]imidazol-2-amine
10 The mixture containing 4-(4-(methylamino)-3-nitrophenoxy)pyridin-2-amine
(leq) and l-isopropyl-3-isothiocya3aatobenzene (leq) in methanol v^as stirred at room
temperature for 16 hoxxrs to form the corresponding thiourea. To it was then added iron
(III) chloride (1.2eq) and stirred for another 4 hours. The mixture was then concentrated
and partitioned between saturated sodium carbonate and ethyl acetate. The organic layer
15 was separated and washed with water and brine, dried over sodium sulfate and
concentrated to give brown crude solid. Purification by trituration with toluene to give 5-
(2-aminopyridin-4-yloxy)-N-(3 -isopropylphenyl)- 1 -methyl- 1 H-benzo [d] imidazol-2-
amine as brown solid. HPLC = 3.63min: MS: MIT" = 374.
2. Synthesis of tert-butyl 4-((4-(2-(3-isopropylphenylamino)-l -methyl- IH-
20 benzo[d]imidazol-5-yloxy)pyridin-2-ylcarbamoyl)methyl)piperidine-l-carboxylate
To a mixture of 2-(l-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (leq) inN,N-
dimethyl formamide and N^N^disopropylethylamine (4eq) was added HATU (2eq) and
the mixture was stirred at ambient temperature until it becomes homogeneous. To it was
added 5 -(2-aminopyridin-4-yloxy)-N-(3 -isopropylphenyl)- 1 -methyl- 1 H-benzo-
25 [d]imidazol-2-amine (leq) and 4-(dimethylamino)pyridine (0.05eq) and the resulting
-65-
wo 2005/037273
PCT/US2004/034179
mixture was stirred at room temperature for 16h. The reaction mixture was then
concentrated and partitioned between ethyl acetate and water. The organic layer was
dried over sodium sulfate and the resulting tert-butyl 4-((4-(4-(methylamino)-3-
nitrophenoxy)pyridin-2-ylcarbamoyl)methyl)piperidine-l-carboxylate was pxirified by
HPLC. HPLC-4.63min;MS:
3. Synthesis of N-[4-({2-[(3-isopropylphenyl)amino]-l-methyl-lH-benzimidazol-5-
yl}oxy)pyridin-2-yl]-2-piperidin-4-ylacetamide
To tert-butyl 4-((4-(4-(methylaniino)-3-nitrophenoxy)pyridin-2-ylcarbamoyl)-
methyl)piperidine-l-carboxylate (leq) in water and acetonitrile was added trifluoroacetic
acid (2eq) and stirred at room temperature for 16 hours. The resulting solution was
frozen with liquid nitrogen and the lyophilized sample yielded N-[4-({2-[(3-
isopropylphenyl)amino]-l-methyl-lH-benzirxiidazol-5-yl}oxy)pyridin-2-yl]-2-piperidi
4-ylacetamide. HPLC = 3.49min; MS: MH^ - 499.
Example 30
Synthesis of N-r4-r ( 2-rr3-isoDropYbhenvDamino1- 1 -met hvl- 1 H-henzi midazol-5-
vl } oxv^pvridin-2- vll -2-( 1 -metliYlpiDeridin-4-vnacetamide
1 . Synthesis of 5-(2-aminopyridin-4-yloxy)-lSr-(3 -isopropylphenyl)- 1 -methyl- 1 H-
benzo [d] imidazol-2-amine
The mixture containing 4-(4-(methylamino)-3 -nitrophenoxy)pyridin-2-amine
(leq) and l-isopropyl-3-isothiocyanatobenzene (leq) in methanol was stirred at room
temperature for 16 hours to form the corresponding thiourea. To it was then added iron
(III) chloride (1 .2eq) and stirred for another 4 hours. The mixture was then concentrated
and partitioned between saturated sodium carbonate and ethyl acetate. The organic layer
was separated and washed with water and brine, dried over sodium sulfate and
concentrated to give brown crude solid. Purification by trituration with toluene to give 5-
-66-
wo 2005/037273
PCT/US2004/034179
(2-aminopyridin-4-yloxy)-N-(3 -isopropylphenyl)- 1 -methyl- 1 H-benzo[d]imidazol-2-
amine as brown solid. HPLC = 3.63min; MS: MH'^ = 374.
2. Synthesis of tert-butyl 4-((4-(2-(3 -isopropylphenylamino)- 1 -methyl- 1 H-
benzo[d]imidazol-5-yloxy)pyridin-2-ylcarbamoyl)methyl)piperidine-l-carboxylate
5 To a mixture of 2-(l-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (leq) in N^N-
dimethyl formamide and N,N,disopropylethylamine (4eq) was added HATU (2eq) and
the mixture was stirred at ambient temperature until it becomes homogeneous. To it was
added 5 -(2-aminopyridin-4-yloxy)-lSf-(3 -isopropylphenyl)- 1 -methyl- 1 H-benzo [d] -
imidazol-2-amine (leq) and 4-(dimethylamino)pyridine (O.OSeq) and the resulting
10 mixture was stirred at room temperature for 16h. The reaction mixture was then
concentrated and partitioned between ethyl acetate and water. The organic layer was
dried over sodium sulfate and the resulting tert-butyl 4-((4-(4-(methylamino)-3-
nitrophenoxy)pyridin-2-ylcarbamoyl)methyl)piperidine- 1 -carboxylate was purified by
HPLC. HPLC = 4.63min;MS: MH^ = 599.
15 3. Synthesis of N-(4-(2-(3-isopropylphenylamino)-l-methyl-lH-benzo[d]imidazol-5-
yloxy)pyridin-2-yl)-2-(piperidin-4-yl)acetamide
To tert-butyl 4-((4'-(4-(methylamino)-3-nitrophenoxy)pyridin-2-ylcarbamoyl)-
mefhyl)piperidine-l -carboxylate (leq) in water and acetonitrile was added trifluoroacetic
acid (2eq) and stirred at room temperature for 16 hours. The resulting solution was
20 frozen with liquid nitrogen and the lyophilized sample yielded N-(4-(2-(3-
isopropylphenylamino)- 1 -methyl- 1 H-benzo [d]imidazol-5-yloxy)pyridin-2-yl)-2-
(piperidin-4-yl)acetamide. HPLC = 3.49min; MS: MH^ - 499.
4. Synthesis of N-[4-({2-[(3-isopropylphenyl)amino]-l -methyl-lH-benzimidazol-5-
yl}oxy)pyridin-2-yl]-2-(l-methylpiperidin-4-yl)acetamide
25 To the mixture containing N-(4-(2-(3 -isopropylphenylamino)- 1 -methyl- IH-
benzo[d]imidazol-5-yloxy)pyridin-2-yl)-2-(piperidin-4-yl)acetamide (leq), glacial acetic
acid (2 eq), and formaline (7.5eq) in tetrahydrofiiranrmethanol (1:1) was added sodixrai
cyanoborohydride (2eq) and stirred at room temperature for one hour. Reaction
neutralized with satmated sodium carbonate solution and extracted with ethyl acetate.
30 The organic layer was washed with brine, dried over sodium sulfate and concentrated to
-67-
wo 2005/037273
PCT/US2004/034179
give crude product. Purification by HPLC to yield N-[4-({2-[(3-isopropylphenyl)amino]-
1 -methyl- 1 H-benzimidazol- 5 -yl } oxy)pyridin-2-yl] -2-( 1 -mefhylpiperidin-4-yl)acetamide .
HPLC = 3.51min;MS: MH'' = 513.
Example 31
5 Synthesis of N- ( 4-[r2- 1 [2-fluoro-5 -(trifluoromethyDphenvn amino 1-1 -methyl- 1 H-
benzimidazol-S -yl)oxy1pyridin-2-yU -2- \( 2S V2-(hydroxymethvlWrrolidin- 1 -
yllacetamide
L-Prolinol (3.0 eq) was added to a mixture of 2-cllloro-N-{4-[4-(methylamino)-2-
nitrophenoxy](2-pyridyl)}acetamide (1 eq) in acetonitrile. The resulting mixture was
brought to 60°C. LC/MS showed quantitative conversion after stirring for 1 hour. The
reaction was concentrated to about half the volume of solvent and then partitioned
15 between water and ethyl acetate. The aqueous layer was extracted 2x wdth ethyl acetate.
The organic layers were combined and washed with water followed by saturated sodium
chloride, dried over magnesium sulfate and concentrate to yield pure product. MS:
MH''= 402.2.
-68-
wo 2005/037273
PCT/US2004/034179
Step 2:
OM
HO.
HO
H
N
H2, Pd/C
MeOH
N
H
H
N.
N O
2-(2-Hydroxymethyl-pyrrolidm- 1 -yl)-N-[4-(4-methyl^^
pyridin-2-yl]-acetaraide was hydrogenated in methaniol in the presence of Pd/C for 4
hours. The catalyst was removed via filtration through CeHte and filtrate was
concentrated to give N-[4-(3-Amino-4-methylainino-phenoxy)-pyridin-2-yl]-2-(2-
hydroxymethyl-pyrrolidin-l-yl)-acetamide. MS: MH^= 372.4.
Step 3:
H,N
HO
H
N.
li^N o
XX
MeOH/RT
2. FeCl3/MeOH/RT
HO.
H
2-Fluoro-5-(trifluoromethyl)phenyl isothiocyariate was added to a solution of N-
[4-(3-Amino-4-niethylaniino-phenoxy)-pyridin-2-yl]-2-(2-hydroxymethyl-pyrroHdin-^
yl)-acetamide in methanol. Reaction was stirred at room temperature for 15 hours.
Tliiourea formation was confirmed by LC/MS. Ferric chloride was added and the
resulting mixture was stirred at room temperature for 4 hoxors. After cyclization was
complete by LC/MS the reaction mixture was concentrated and aqueous sodiimi
carbonate was added until basic pH. The reaction mixture was partitioned between ethyl
acetate and water. The organic layer was washed with water then brine, and dried over
magnesium sulfate and concentrated. The crude product was purified by reverse phase
HPLC. MS: MH^= 559.3.
-69-
wo 2005/037273
PCT/US2004/034179
Example 32
Synthesis of C2 S VN- 1 4- rr2- 1 [2 -fluoro-5 -( txifluoromethyPphenyll amino > ■ 1 -methyl- 1 H-
benzimidazol"5-yl'loxy1pyridin"2"yl>piperidine-2-carboxamide
Step 1
Boc'
BOP, DIEA
DMF, 60° C
OoN
HN
N-Boc homoproline (1.0 eq) was added to a solution of the amino pyridine (1.0
eq), BOP (2.0 eq) and diisopropylethylamine (3.0 eq) in DMF. The solution is heated
oyemight at 60^C. The solution is concentrated on a rotovap to about one fourth its
10 original volume, then poured into water and EtOAc. The layers are separated and the
organic is washed with water and then brine, dried over MgS04, filtered, silica added, and
the solution is concentrated. The product is then purified by column chromatography
(gradient of 2% MeOH: DCM -> 10% MeOH: DCM) to yield the desired product MH+ -
472.5.
15 Step 2:
H2. Pd/C
MeOH
-70-
wo 2005/037273
PCT/US2004/034179
The nitroaniline was hydrogenated in methanol in the presence of Pd/C for 4
hours. The catalyst was removed via filtration through Celite and filtrate was
concentrated to give phenylenediamine. MS: MH'*'= 442.4.
Step 3:
MeOH/RT
F.C
2. FeCia/MeOH/RT
3. HCi/dioxane
2-Fluoro-5-(trifluoromethyl)phenyl isothiocyanate was added to a solution of
phenylenediamine in methanol. Reaction was stirred at room temperature for 15 hours.
Thiourea formation was confirmed by LC/MS. Ferric chloride was added and the
resulting mixture was stirred at room temperature for 4 kours. After cyclization was
10 complete by LC/MS the reaction mixture was concentrated and aqueous sodium
carbonate was added until basic pH. The reaction mixture was partitioned between ethyl
acetate and water. The organic layer was washed with water then brine, and dried over
sodium sulfate and concentrated. The protecting group is removed by treating the crude
product with HCl in dioxane for 3 0 minutes at room temperature whereupon the solvent
15 is removed. The crude product was purified by reverse phase HPLC. MS: MFt= 529.5.
Example 33
Synthesis of N- 14-( 1 2- rr2-fluoro-5-pvridin-4-vlphenvl^amino1 - 1 -methvl- 1 H-
benzimidazol"5-yl>oxy)Dvridin-2-yl]acetamide
-71-
wo 2005/037273
PCT/US2004/034179
Step 1 :
5-Bromo-2-fluoronitrobenzene (1.0 eq), 4-pyridylboronic acid (2.0 eq), and [l,r-
bis(diphenylphosphino)ferocene] dichloro palladiiun (II) complex with DCM are mixed
5 in ethyleneglycol dimethylether and 2M aqueous sodium carbonate (4.0 eq). The solution
is purged with argon for 20 minutes and then heated overnight at 1 OO^C. At this time the
reation mixture is cooled and then poured into water and EtOAc. The layers are
separated and the organic is washed with water and then brine, dried over MgS04,
filtered, silica added, and the solution is concentrated. The product is then purified by
10 column chromatography (gradient of 1% MeOH: DCM -> 10% MeOH: DCM) to yield
the desired product. MS: MH^-- 219.2.
Step 2:
The nitrophenyl compoimd was hydrogenated in methanol in the presence of Pd/C
15 for 4 hours. The catalyst was removed via filtration through Celite and filtrate was
concentrated to give the desired aniline. MS: MH^= 189.2.
Step 3:
The aniline (1.0 eq) was cooled in a biphasic raixture of dichloromethane and
20 sodium carbonate (4.0 eq) to 0^ C. At this time thiophosgene (1.0 eq) was added. The
-72-
wo 2005/037273
PCT/US2004/034179
solution was allowed to stir for 30 minutes at which time the phases were separated and
)
the organic phase was dried over magnesiimi sulfate.
Step 4:
MeOH/RT
2. FeCis/MeOH/RT
H
10
15
2-fluoro-5-(4-pyridyl)phenyl isothiocyanate was added as a solution in dcm to a
solution of phenylenediamine in methanol. Reaction was stirred at room temperature for
15 hours. Thiourea formation was confirmed by Ic/ms, Ferric chloride was added and
the resulting mixture was stirred at room temperature for 4 hours. After cyclization was
complete by Ic/ms the reaction mixture was concentrated and aqueous sodimn carbonate
was added until basic ph. The reaction mixture was partitioned between ethyl acetate and
water. The organic layer was washed with water then brine^ and dried over magnesium
sulfate and concentrated. The cmde product was purified by reverse phase HPLC. MS:
MH+- 469.5.
Example 34
Synthesis of N-[4-r 1 2'\(3 -tert-butvlnhenvnaminol ■ 1 -metfavl- 1 H-benzimidazol-5-
vl 1 oxY'lPYridin-2-yll -2-f 4-methy Ipiperidin- 1 - vHacetamide
Step 1 :
o
TEA, THF
-73-
wo 2005/037273
PCT/US2004/034179
Chloroacetyl chloride (1.4 eq) was added dropwise over 15 minutes to a stirring
solution of the amino pyridine (1.0 eql) and triefhylamine (2.7 eq) in. THF (1.2 L) at room
temperature. After 2 hours LC shows 80% conversion to the desired product with a small
amount of starting material and some bis acylated product (<10%) as well. The solution
is concentrated on a rotovap to about one fourth its original volume, then poured into
water and EtOAc. The layers are separated and the organic is washed with water and
then brine, dried over MgS04, filtered, silica added, and the solution is concentrated. The
product is then purified by column chromatography (gradient of 30?^ EtOAc: hexanes ->
60% EtOAc hexanes) to yield the desired product (39% yield).
Step 2;
KaCOs.DMF
eo'^c
09N
4-Methylpiperidine (2.8 eq) was added to a mixture of 2-chloro-N-{4-[4-
(methylamino)-2-nitrophenoxy](2-pyridyl)}acetamide (1 eq), and potassium carbonate
(3.3 eq) in dimethylformamide. The resulting mixture was brought to 60^C. LC/MS
showed quantitative conversion after stirring for 1 hour. The reaction was partitioned
between water and ethyl acetate. The aqueous layer was extracted 2x witb ethyl acetate.
The organic layers were combined and washed with water followed by saturated sodium
chloride, dried over sodium sulfate and concentrated. The crude product was passed
through a plug of silica and eluted with 10% methanol/ methylene cliloride. MS: MH =
400.2.
Step 3 :
OoN
H?., Pd/C
EtOH
N-{4-[4-(methylamino)-3-nitrophenoxy](2-pyridyl)}-2-(4-methylpiperidyl)acet-
amide was hydrogenated in the presence of Pd/C for 4 hours. The catalyst was removed
-74-
wo 2005/037273
PCT/US2004/034179
via filtration and filtrate was concentrated to give N-{4-[3-aminO'-4-(methyl-
arni*nn'inhenoxvir2-nvridvlU-2-r4-methYlDiDeridvnacetaimde. MS: MH^= 370.2.
Step 4:
H
NCS
MeOH/RT
2. FeCla/MeOH/RT
3-(tert-Butyl)benzenisothiocyanate was added to a solution of N-{4-[3-amino-4-
(methylamino)phenoxy](2-pyridyl)}-2-(4-metliylpiperidyl)acetamide in methanol.
Reaction was stirred at room temperature for 15 hours. Thiourea formation was
confirmed by LC/MS, Ferric chloride was added and the resulting mixture was stirred at
room temperature for 4 hours. After cyclization was complete by LC/MS the reaction
mixture was concentrated and aqueous sodium carbonate was added imtil basic pH. The
reaction mixture was partitioned between ethyl acetate and water. The organic layer was
washed with water then brine, and dried over sodium sulfate and concentrated. The cmde
product was purified by reverse phase HPLC. MS: MH-H= 527.2.
Examples 35-68
The gylcinamides in Examples 35-68 were synthesized in a manner similar to that
described above using the indicated starting materials and reagents.
Example 35
Synthesis of N- r4-C { 2- r( 2-fluoro- 5 -isopropylphenynaminol - 1 -methvl- 1 H-benzimidazol-
5 "Vl > oxy)pyri din-2-yn -2 4-methylDiperidin- 1 - vD acetamide
1.
F
NCS
MeOH/RT
: ^
2. FeCl3/MeOH/RT
W //
N-A^ O
MS: MH =531.1.
-75-
wo 2005/037273
PCT/US2004/034179
Example 36
Synthesis of 2-r 4-methvlpir)eridin- 1 -vlVN- 1 4-rri -methvl-2- ( \4-
(trifluoromethvDphen yn amino \ - 1 H-benzimi da2ol-5-vDoxv1pvridin-2-vl \ acetajni de
N'
H
H
F3C
1.
NCS
MeOH/RT
2. FeCis/MeOH/RT
MS: MH^= 539.1.
Example 37
Sy nthesis of N- \4-( 1 2- rr4-fluoro-3 -isoprop vlphenvDaminol - 1 -methyl- 1 H-benzimidazol-
5-yUoxy)pyridin-2-yl1-2-r 4-methylpiperid in- 1 -vnacetamiHfi
NCS
MeOH/RT
2. FeCis/MeOH/RT
MS: Mir'= 531.1.
Example 38
Synthesis of N- (4- 1(2- 1 r2-fluoro-5 -ftrifluoromethynphenyll amino \ - 1 -methyl- 1 H-
benzimidazQl-5-yn Qxy1pyridin-2-yl > -2-r 4-methylpiperidin- 1 -yDacetamide
H9N,
N'
H
.0
N O
N'
T-FsC^^NCS F3C-
MeOH/RT
^
2. FeCla/MeOH/RT
N
HN-<'
N
O.
O
MS: MH^= 557.1.
-76-
wo 2005/037273
PCT/US2004/034179
Example 39
Synthesis of N- 1 4- [(2- 1 r2.4-difluoro-5-r trifluoromethyDphenyll amino ] - 1 -methyl- 1 H-
benzimidazQl-5-yDQxy]pyridin-2"yll -2-f4-methylpiperidin- 1 -yPacetamide
H
O
N O
MeOH/RT
, *-
2. FeCla/MeOH/RT
MS: MH^- 575.0.
Example 40
Synthesis of N-r4"({2-r(2.4-difluoro-5-isopropylphenyl)amino1-l-methvl-lH-
benzimidazol-5 -yll oxy)pyridin-2-yn -2-r4-methylpiperidin- 1 -ypacetamide
H
O
N O
1. ^^'^^*:^NCS
MeOH/RT
2, FeGls/MeOH/RT
MS: MH^- 549.1.
Example 41
Synthesis of N- r4-( (2- [^5 -tert-butyl-2-fluorophenyl)aminol - 1 -methyl- 1 H-beruzimidazol-
5-yll oxy)pyridin"2-yl]-2-(' 4-methylpiperidin- 1 -yDacetamide
HoN
N
H
O
H
N
N O
1. "^ppO-^cs
MeOH/RT
: .
2. FeCb/MeOH/RT
MS: MH+= 545.1
-77-
wo 2005/037273
PCT/US2004/034179
Example 42
Synthesis of r4-(' (2-f"r3"tert-butvlphenvnammQl-l -methvl-lH-beiizi
vUQXV^pyridin"2"Vl1"N-2-N~2--diethvlglvcmamide
OoN
H
+ HNEt2
K2CO3 ,DMF
60°C
N'
H
MS: MH+= 374.2
H2. Pd/C
EtOH
N
H
,0
H
N
N O
NCS
/
MeOH/RT
2. FeCIa/MeOH/RT
MS: MH+= 344.1
MS: MH+= 501.1
Example 43
Synthesis of N-2-.N-2— diethvl-N- 1 — r4-( ( 2- fa-fluor o- 5 -isopr opylpheny Daminol - 1 -
methyl- 1 H-benzimidazol-5-yU oxy)pyridin-2-yn glycinamide
MS: MH =505.1.
-78-
wo 2005/037273
PCT/US2004/034179
Example 44
Synthesis of N-2~.N-2— diethvl-N- 1 — (4- [(1 -methvl-2- ( [4-
CtrifluoromethvDphenyn amino ) - 1 H-benzimidazol-5- vHox v1 pyri dm-2- yl \ gly cinamide
N
H
N
^ ^^NCS
MeOH/RT
: ^
2. FeCb/MeOH/RT
P3C
HN—
H
N
MS: MH^- 513.0.
Example 45
Synthesis of N-2-.N-2--diethyl-N-l-44-(U-r(^4-fluoro-34sopropyte henyna^^
methyl- 1 H-benzimidazol-5 -yl > oxv)pyridin-2-yn glycinamide
N
H
O
H
N
N O
N'
^- II
"NCS
MeOH/RT
— ^
2. FeCls/MeOH/RT
MS:MH^-505.L
Example 46
Synthesis of N-2-.N-2— diethyl-N-1— l4-rr2-(r2-£IuQro-5-
CtrifluoromethyDphenynamino 1 - 1 -methyl- 1 H-benzimidazQl-5-ynoxy1pyridin-2-
yl I glycinamide
H
H2N
N
H
1.
FgC^NCS FsC-\ H
MeOH/RT ( N^-.,^^-^^O.^^^^N.^^^
2. FeCls/MeOH/RT
N
/
MS: MH'^^ 531.1.
-79-
wo 2005/037273
PCT/US2004/034179
Example 47
Synthesis of r4-a 24r3-tert-butvlphenvnammo1-l-methvl-lH-ben^^
yl>oxv^pyridin-2-vl1-N~2— ethvl-N-2--propvlglvcinamide
H
N
N O
CI
HNEts
K2CO3 .DMF
60°C
O2N.
H
H
N
N O
N'
MS: Mir'= 388,3
OoN.
N
H
H
N
N O
H2. Pd/C
EtOH
H9N
N
H
.0
H
N
N O
N
MS: MH^- 358.2.
N O
N
NCS
MeOH/RT
2. FeCls/MeOH/RT
N
/
H
N O
MS: MH'"= 515,1.
Example 48
Synthesis of N-2— ethvl-N-l--r4-ri24f2-fluoro-5-isopropylDhenynammo1-l-^^
1 H-benzimidazol-5 -yl } oxy)pyridm-2-yn "N-2— propyl Rlycinamide
F
NCS
MeOH/RT
2. FeCla/MeOH/RT
HN— <^
N
N
/
H
N
N O
N'
MS: MH:^= 519.1
-80-
wo 2005/037273
PCT/US2004/034179
Example 49
Synthesis of ethvl-N- 1 — ( 4- [( 1 -methvl-2" I r4-rtri fluoromethYnphenYn amino 1 - 1 H-
benzimida2:ol"5-vl)oxv1pvridin--2-yl>-N-2— propylglycinainide
HoN.
N
H
H
N
N O
N
F3C
1.
F3C
NCS
MeOH/RT
2. FeCls/MeOH/RT
HN
N
/
H
MS: MH^= 527.1.
Example 50
Synthesis of N-2— ethyl-N-1 — [4-( (2-[(4-fluoro-3-isopropylphenyl')amino1-l -methyl-
1 H-benzimidazQl-5 -yl } oxy)pyri din-2-yl] -N-2—propylglycinamide
H2N
N
H
H
N
N O
II
NCS
MeOH/RT
2. FeCla/MeOH/RT
HN
N
^/
N
/
O
H
N
N O
MS: MH^= 519.1.
Example 51
Synthesis of N-2— ethyl-N- 1—14- \(2- ( r2-fluoro-5-(trifluQromethyl)phenyl1 amino > - 1 -
methyl- lH-benzimidazQl-5-yl)oxy1pyridin-2-yU-N-2—propylglycinamide
H2N
N
H
o
H
N
N o
N
F3C
MeOH/RT
H
2. FeCla/MeOH/RT
N
N
li^N O
MS: MH:'= 545.1
-81-
wo 2005/037273
PCT/US2004/034179
Example 52
Synthesis of N-1 — l4-['f2- 1 r2.4-difluoro-5-(trifluoromethvl)phenYl1amino) - 1-methvl-lH^
beii2:imidazol"5-vl)oxv]pvridin-2-vU-N-2— ethvl-N~2 — propvlglycinamide
MS: MH""- 563.0.
Example 53
Synthesis of N- 1 — r4-( ( 2- [(2 ..4"difluoro-5 -isoprop ylphenyl') amino] - 1 -methyl- 1 H-
benzimidazol-5-yl)oxy)pyridin"2-yl]-N-2— ethyl-N-2— propylglycinamide
MS:MH
Example 54
Synthesis of N-1 — \4-( i2-\(5 -tert-butyl-2-fluorophenyl)amino1- 1 -methyl- 1 H-
benzimidazol-5-yUoxY')pyridin-2-yl1-N-2— ethyl-N-2— propylglycinamide
MS: MH"- 533.1.
-82-
wo 2005/037273
PCT/US2004/034179
Example 55
Synthesis of N- \4'-({2'-\( 5-tert"butyl"2'-fluorophenyl')amino]- 1 -methyl- 1 H-benzimidazol-
5 -yl > oxy)pyridin-2-yl1 -2-piperidin" 1 -ylacetamide
H'
H
H
N
N
F
NCS
/
MeOHyRT
2. FeCia/MeOH/RT
MS: MH^= 531.2.
Example 56
Synthesis of N-[4-r 1 2-[(2-fluoro-5-pyridin-4-ylphenyl)ammo1- 1 -methyl- 1 H-
benzimidazol-5-yll oxy')pyridin-2-yl1 -2-piperidin- 1 -ylacetamide
N
H
H
N
N O
N
1. N_J^^L/"^
MeOH/R-
H
2, FeCls/MeOH/RT N
F HN—
N
/
MS: MH^= 552.1
Example 57
Synthesis of N- [4-^ 1 2- [(5-tert-butyl-2-fluorophenyDamino1 - 1 -methyl- 1 H-benzimidazol-
5-yl)Qxy)pyridin-2-yn-2-r3.5-dimethylpiperidin- 1 -yPacetamide
OoN
N
H
O
H
O
CI
H
N,
K2CO3 ,DMF
60°C
OM
H
H
O
N O
MS: MH^- 414.1.
N
H
,0
H
N
Hg. Pd/C
EtOH
MS: MH'^^ 384.2
-83-
wo 2005/037273
PCT/US2004/034179
1.
/
F
NCS
MeOH/RT
2. FeCla/MeOH/RT
MS: MH^- 559.2.
Example 58
Synthesis of 2-(3.5-dimethYlpiperidin-l-vlVN44-rf2-{r2-fluoro-5-
rtrifluoromethyDphenvllanimo} - 1 -methyl- 1 H-benzimidazol-5-Yl')oxYlpYridin-2-
yUacetamide
HoN
FgC^^NCS F3C
MeOH/RT
N
2. FeCla/MeOH/RT
O
H
N
N O
MS: MH^- 571.1
10
Example 59
Synthesis of 2-r3.5-dimethylpiperidin-l-yl)--N-r4-a2-rr4-fluoro-3--
isQpropylphenyDamino1"l-methyl-lH-benzimidazol-5-yUoxy)pyridin-2-yl]acetaniide
H
21
H
H
N
N O
1.
"'NCS
MeOH/RT
^
2. FeCla/MeOH/RT
MS: MH"- 545.2,
Example 60
15 Synthesis of 2-azetidin-l-yl-N44-ri2-r(54ert-butyl-2-fluorophenynaminQl-l-methyl-lH
benzimidazol-5-yUoxy')pyridin-2"yllacetainide
O2N
H
CI
HN
□
K2CO3 .DMF Y^^T^'t'^
60°C
N
H
-84-
wo 2005/037273
PCT/US2004/034179
MS: MH^= 358,1.
H
O9N.
N
H
Hg, Pd/C
EtOH
HoN.
N
H
.0
H
N
N O
MS: MH^- 328.1.
H
N
H
,0
1.
N O
NCS
^AeOH/RT
^
2. FeCla/MeOH/RT
H
MSiMH = 503.1.
Example 61
Synthesis of 2-azetidin- 1 -yl-N- (4- ["(2- ( [3 -fluoro-4-(trifluoromethvl)phenYl1 amino > - 1 -
methyl- 1 H-benziniidazol"5-yl)oxy1pvridin-2-yl } acetamide
MS: MH =515.0.
Example 62
Synthesis of 2-azetidin-l-yl-N-[4-r(2-r(2-fluorO"5-pyridin-4"ylphenynaminoVl-methyl-
lH-benzimidazol-5-yl>oxy)pyridin-2-yl1acetamide
MS: MH =524.1.
-85-
wo 2005/037273
PCT/US2004/034179
Example 63
Synthesis of 2-r4"rdimethylammo)piperidm-l-yl]-N-l4-r(2"([2-fluorO'-5-
(trifluoromethyl)phenyl] amino > - 1 -methyl- 1 H"benzimidazol-5'yl)oxy1pyridin-2-
yllacetamide
02N^ ^
N O
CI
K2CO3 ,DMF
60°C
N O
N'
MS: MH'"= 429.1.
H
,0
H
N
N O
N
N'
H2. Pd/C
EtOH
N
H
O
H
N
N O
N'
N
MS: MH^- 399.2.
N
H
N O
N'
F
3^ ' '^^^ F^C
''•FgC'^^NCS
MeOH/RT
—
2. FeCls/MeOH/RT
N
HN—
N
O
H
N
O
N'
I
10
MS: MH^- 586.1.
Example 64
Synthesis of 2- \4-( dimethylamino')piperidin- 1 -ylj-N- [4-(' (2- ['(2-fluorO"5"pyridin-4-
ylphenyl)amino1-l -methyl" 1 H-benzimidazol-5-yUoxy)pyridin-2"yl1acetamide
H
H2N
H
1.
N
NCS
MeOH/RT
2. FeCls/MeOH/RT
F HN-<''
15
MS:MH^= 595.2.
-86-
wo 2005/037273
PCT/US2004/034179
Example 65
Synthesis of N- 14- [(2- ( r2-fluoro-5-(trifluoromethvl)phenyl1 amino > - 1 -methyl- 1 H-
benzimidazol-5-yl)oxy1pyridin-2-yU -2-( 4-methoxypiperidin- 1 -yPacetamide
F
•TFA
l-N-Boc-4-hydroxypiperidine (1.0 eq; O.Takuna, H. Yoshitaka, Y. Kaoru, O.
Yoshitaka, M. Hideaki. WO2003018019. Preparation of Substituted 2-(lJ-
Dioxaperhydro-1 ,4-thiazepin-7-yl)acetamides for Treating Inflammatory Respiratory
10 Disease) in THF (10 mL) was added to NaH (2.7 eq) in THF (20 mL) at 0°C. After 20
min, Mel (1.1 eq) was added drop wise. This mixture stirred for 2 h and was then
quenched with H2O and extracted twice with EtOAc. The organic layer was dried over
sodiiam sulfate and concentrated. MS: MH"^= 216.1 (MHT^-^-Bu). The material was
dissolved in CH2CI2 and TFA (3:1) and stirred ovemight. The solvent was then removed
15 by rotory evaporation to give a clear oil. MS: MHr*'= 1 16.0.
MS: MH =416.1.
-87-
wo 2005/037273
PCT/US2004/034179
O2N
,0
N
H
H
N
N O
N'
O
H2. Pd/C
EtOH
N
H
H
N
N
O
MS: MH''= 386.2.
H
,0
N O
O
F
■30 - NCS
MeOH/RT
F3G
H
N
2. FeCls/MeOH/RT
HN—
N
O k
MS: Mir'= 573.1.
Example 66
Synthesis of N- 14- 2- 1 r2-cMorQ-5-r trifluoromethynphenvn amino \ - 1 -methvl- 1 H-
benziniidazol-5-vDo xv1pyridin-2-yn-2-r4-niethoxvpiperidin-l-vnacetamide
N
H
Q
CI
O
,0:
MeOH/RT
F,C
CI
2. FeCls/MeOH/RT
HN— <
N
N
H
N O
O'
MS: MH''= 589.1
Example 67
Synthesis o f N-(4-ra-fr2-fluoro-5-arifluoromethynphenyl1aminoVl-me&^^
benzimidazol-5-vnoxy1pyridin-2-yn-2-r3-methoxyazetidin-l-ynacetamide
Boc.
NaH, THF,
Mel,
'OH
Boc.
N— 1
TFA, CH2CI2
HN-
OMe
OMe
•TFA
-88-
wo 2005/037273
PCT/US2004/034179
l-N-Boc-3-hydroxyazetidine (1.0 eq) in THF (10 mL) was added to NaH (2.6 eq)
in THF (20 mL) at O^^C. After 20 min, Mel (1.1 eq) was added dropwise. This mixture
stirred for 2 h and was then quenched with H2O and extracted twice with EtOAc. The
organic layer was dried over sodium sulfate and concentrated. MS: MHT*"" 132.1 (MR^-t-
Bu). The material was dissolved in CH2CI2 and TFA (3:1) and stirred overnight. The
solvent was then removed by rotary evaporation to give a clear oil. MS: MH'^= 87.9.
HN
K2CO3 ^DIVIF
OoN
•TFA
OMe 60°C
OMe
MS: MH^= 388.1.
OMe
H2, Pd/C
EtOH
OMe
MS: MH""- 358.2.
OMe-
l-FsC^^^NCS
MeOH/RT
F^C
2. FeCls/MeOH/RT
H
U^N O ^oMe
MS: MH'"= 545.1.
Example 68
Synthesis of N- ( 4- r(2- ( r2-chlorO"5 -(trifluoromethvDphenvll amino > - 1 -methyl- 1 H-
benzimidazol-5-yl)oxy]pyridin-2-vU-2-f3"methoxyazetidin-l"yl)acetamide
FoC^^
CI
OMe-
■30 - NCS
MeOH/RT
2. FeCIs/MeOH/RT
OMe
MS: MIT'^ 561.1.
-89-
wo 2005/037273
PCT/US2004/034179
Example 69
Synthesis of N- 1 4-rr 1 -methvl-2-- 1 r4-(trifluoromethvl)phenvl1 amino 1-1 H-benzimidazol-S-
vl)oxv]pYridin-2-vUpropanamide
F
5 1. Synthesis of N-[4-(4-Methylamino-3-nitro-phenoxy)-pyridin-2-yl]-propionamide
2. hydrazine
71a 71b
To a stirring suspension of 71a (1 eq) and zPr2NEt (1.5 eq) in dioxane (4 mL) was
added propionyl chloride (2 eq) and mainainted at rt overnight. Hydrazine (1 eq) was
added and stirred for 2 hours. Crude product was concentrated down, and was then
10 partitioned between EtOAc and saturated aqueous Na2C03. The layers were separated
and the aqueous layer was extracted with EtOAc (3 X). The combined organic portions
were washed with brine, dried (MgS04), concentrated, and the resulting residue was
adsorbed onto SiOa. Purification by flash chromatography (0.5 : 99.5, 0.75 : 99.25, 1 :
99, 2 : 98, methanol-CH2Cl2) gave 310 mg of a bright orange solid as 71b: NMR (300
15 MHz, CDCI3) □ 8.35 (br s, 1 H), 8.13 (d, J= 5.77 Hz, 1 H), 7.91 (d, J= 2.74 Hz, 1 H),
7.68 (d, J= 2.2 Hz, 1 H), 7.38 (dd, /= 2.74, 2.75 Hz 1 H), 7.11 (d, J= 9.61 Hz, 1 H),
6.68 (dd, J= 2.47, 2.47 Hz, 1 H), 3.065 (d, J= 3.85 Hz, 3 H), 2.40 (m, 2 H), 1.141 (m, 3
H).
-90-
wo 2005/037273
PCT/US2004/034179
2. Synthesis of N-{4-[(l-metiiyl-2-{[4-(trifluoromethyl)phenyl]amino
berLzimidazol-5 -yl)oxy]pyridin-2-yl } propanamide
O2N.
MeHN
N O
1. 10% Pd/C, H2, MeOH
2. F3C
NCS
71b
MeOH
3, FeCIs, pyridine
71c
A suspension of propionamide 71b (1 eq) and 10% Pd/C (10 mol %) in methanol
(4 mL) was charged with H2 and the resulting reaction mixture was maintained under a
H2 atmosphere for 1 h at rt. The mixture was filtered and the remaining soHds washed
thoroughly with EtOAc and methanol. The combined organic portions were evaporated
to afford 272 mg of a brown residue as the phenylene diamine, which was carried forward
without further pxarification.
The above diamine (1 eq) was dissolved in methanol (2 mL) and 4-trifluoromethyl
phenylthioisocyanate (1 eq) was added. The reaction was maintained for 16 h. Pyridine
(3 eq) was added to the reaction, followed by ferric chloride (1.1 eq). The resulting dark
reaction mixture was maintained at rt for 16 h, then suspended in saturated aqueous
NazCOs solution, and filtered with Celite. The remaining solids were washed with
EtOAc and the combined filtrate was partitioned and separated. The aqueous portion was
extracted with EtOAc (3 X) and the combined organic portions were washed with brine,
dried (MgS04), and evaporated. Purification by semi-prep HPLC gave 71c as the TFA
salt. LCMS m/z 456.2 (MH^, = 3.21 min.
Example 70
Synthesis of N"f4-{^l-methvl"2-((4-^^trifluoromethvl)thio^phenvUamino)"lH-
benzimidazol-5-ynoxv>pvridin-2-vl)propanamide
/
-91-
wo 2005/037273
PCT/US2004/034179
Synthesized as described above in Example 69 using 4-trifluoromethylphenyl
isothiocyanate. LCMS m/z 488.2 (MH""), 3.72 min.
Example 71
Synthesis of N- [4-^12- [( 3 -tert-butvlnhenynamino] ■ 1 -methyl- 1 H-benzimidazol-5 -
Synthesized as described above in Example 69 using 3 -/^^/^^-butylphenyl
isothiocyanate. LCMS m/z 444.3 (MH^), 3.47 min.
Example 72
Synthesis of N- r4"( { 2- [(4 -tert-butylphenvDamino] - 1 -methyl- 1 H-benzimidazol-S -
yl } oxy')pyridin-2-yl1propanamide
Synthesized as described above in Example 69 using 4-rerr-butylphenyl
isothiocyanate. LCMS m/z 444.3 (MH^), R^ 3.52 min.
Example 73
Synthesis of N- r4-f 1 2- \( 4>-fluoro-3 -tetrahydrofuran-S -ylphenyPaminol - 1 -methyl- 1 H-
ben2imida2ol--5-yl>oxy)pyridin-2-yl1propanamide
Synthesized as described above in Example 69 using 3-(2-fluoro-5-
isothiocyanato-phenyl)-tetrahydro-furan. LCMS m/z 476.3 (MH"^), R/ 2.73 min.
yl > oxy)pyridin-2 -yl] propanamide
-92-
wo 2005/037273
PCT/US2004/034179
Example 74
Synthesis of 2-methoxv -N- 14- rr 1 -methvl-2- 1 r4"rtrifluQromethvnDhenvn amino > - 1 H-
benzimidazol-5-vDoxv1pvridin-2-vl>acetamide
/
1 . Synthesis of 2-Methoxy-N44-(4-methylamino-3-iiitro-phenoxy)-pyridin-2-yl]-
acetamide
o
HO
/PrgNEt, HATU, DMF
50 °C, o/n
76a
76b
To a solution of rPraNEt (6 eq) and dry DMF (8 mL) was added methoxyacetic
acid (2 eq). The resulting solution maintained at rt for 30 min, at which time HATU (2.2
eq) was added, and continued stirring at rt for 1 hour. 76a (1 eq) was added, the flask
was sealed and the resulting solution was heated to 50 °C overnight. Crude product was
partitioned between EtOAc and water, the layers were separated and the aqueous layer
was extracted with EtOAc (3 X). The combined organic portions were washed with
brine, dried (MgS04), concentrated, and the resulting residue was adsorbed onto Si02.
Purification by flash chromatography (0.5 : 99.5, 0.75 : 99.25, 1 : 99, 2 : 98, methanol-
CH2CI2) gave 640 mg of a bright orange solid as 76b: NMR (300 MHz, CDCI3) □
8.67 (br s, 1 H), 8.15 (d, J- 5.76 Hz, 1 H), 8.04 (br s, 1 H), 7.965 (d, J- 2.75 Hz, 1 H),
7.807 (d, J= 2.2 Hz 1 H), 7.30 (dd, J= 2.75, 2.75 Hz, 1 H), 6.916 (d, J= 9.34 Hz, 1 H),
6.63 (dd, J= 2.47, 2.48 Hz, 1 H), 3.98 (s, 2 H), 3.48 (s, 3 H), 3.06 (d, J= 5.22 Hz, 3 H).
-93-
wo 2005/037273
PCT/US2004/034179
2. Synthesis of 2-methoxy-N-{4-[(l-me1±Lyl-2-{[4<Mfluoromethyl)phenyl]amm^
benzimidaz:ol-5-yl)oxy]pyridin-2-yl}acetamide
F3C
O2N.
MeHN"
.0
H
N.
N O
1. 10% Pd/C, H2, MeOH
2. F3C
HN
NCS
76b
MeOH
3. FeCl3, pyridine
,0
76c
H
N
N O
O
A suspension of methoxyacetamide 76b (1 eq) and 10% Pd/C (10 mol %) in
methanol (4 mL) was charged with H2 and the resulting reaction mixture was maintained
under a H2 atmosphere for 1 h at rt. The mixture was filtered and the remaining solids
washed thoroughly with EtOAc and methanol. The combined organic portions were
evaporated to afford 272 mg of a brown residue as the phenylene diamine, which was
carried forward without further purification.
The above diamine (1 eq) was dissolved in methanol (2 mL) and 4-trifluoromethyl
phenylthioisocyanate (1 eq) was added. The reaction was maintained for 16 h. Pyridine
(3 eq) was added to the reaction, followed by ferric chloride (1.1 eq). The resulting dark
reaction mixture was maintained at rt for 16 h, then suspended in saturated aqueous
NaiCOa solution, and filtered with Celite. The remaining solids were washed with
EtOAc and the combined filtrate was partitioned and separated. The aqueous portion was
extracted with EtOAc (3 X) and the combined organic portions were washed with brine,
dried (MgS04), and evaporated. Purification by semi-prep HPLC gave 76c as the TFA
salt. LCMS m/z 474.2 (MH""), - 2.24 min.
Example 75
Synthesis of N-2 — isopropyl-N- 1 — 14- m -methyl-2- ( [4-
(trifluoromethyPphenyll amino > - 1 H-benzimidazol-5-vnoxy1pyridin-2-yl I glycinamide
/
-94-
wo 2005/037273
PCT/US2004/034179
1. Synthesis of {[4-(4-Metliylamino-3-mtro-phenoxy)-pyridin-2-ylcarbamoy^
carbamic acid tert-butyl ester
77a
HO
O H
Boc
/Pr2NEt, HATU, DMF
50 "C, o/n
H
Boc
77b
To a solution of zPr2NEt (4.5 eq) and dry DMF (75 mL) was added tert-
Butoxycarbonylamino-acetic acid (1.5 eq). The resulting solution maintained at rt for 30
min, at which time HATU (2 eq) was added, and continued stirring at rt for 1 hour. 77a
(1 eq) was added, the flask was sealed and the resulting solution was heated to 50 °C
overnight. Crude product was partitioned between EtOAc and water, the layers were
separated and the aqueous layer was extracted with EtOAc (3 X). The combined organic
portions were washed with brine, dried (MgS04), concentrated, and the resulting residue
was adsorbed onto Si02. Purification by flash chromatography (0.5 : 99.5, 0.75 : 99.25, 1
: 99, 2 : 98, methanol-CH2Cl2) gave 4.1 1 g of a bright orange solid as 77b.
2. Synthesis of 2-Amino-N-{4-[l-methyl-2-(4-trifluoromethyl-phenylamino)-lH-
benzoimida2:ol-5-yloxy]-pyridin-2-yl}-acetamide
1 . 1 0% Pd/C, Ha, MeOH F3C
NCS
77b
MeOH
3. FeCia, pyridine
4. TFA, CH2CI2
NH2
77c
A suspension of 77b (1 eq) and 10% Pd/C (10 mol %) in methanol (4 mL) was
charged with Ha and the resulting reaction mixture was maintained under a H2
atmosphere for 1 h at rt. The mixtxare was filtered and the remaining solids washed
thoroughly with EtOAc and methanol. The combined organic portions were evaporated
to afford 380 mg of a brown residue as the phenylene diamine, which was carried forward
without further purification.
-95-
wo 2005/037273
PCT/US2004/034179
The above diamine (1 eq) was dissolved in methanol (2 mL) and 4-trifluoromethyl
phenylthioisocyanate (1 eq) was added. The reaction was maintained for 16 h. Pyridine
(3 eq) was added to the reaction, followed by ferric chloride (1.1 eq). The resulting dark
reaction mixture was maintained at rt for 16 h, then suspended in saturated aqueous
Na2C03 solution, and filtered with Celite. The remaining solids were washed with
EtOAc and the combined filtrate was partitioned and separated. The aqueous portion was
extracted with EtOAc (3 X) and the combined organic portions were washed with brine,
dried (MgS04), and evaporated.
The above glycine-amide (1 eq was dissolved in CH2CI2 (1 mL) and
trifluoroacetic acid (10 eq) was added. The resulting solution was maintained at rt for 16
h. Crude product was concentrated down, and then neutralized with saturated aqueous
Na2C03 solution. The aqueous portion was extracted with EtOAc (3 X) and the
combined organic portions were washed with brine, dried (MgS04), and evaporated to
give 20 mg of 77c as a brownish semi-solid.
3 . Synthesis of N--2— isopropyl-N-1 — {4-[(l -methyl-2- { [4-(trifluoromethyl)phenyl]-
amino}-lH-benzimida2ol-5-yl)oxy]pyridin-2-yl}glycinamide
F,C
77c
o
NaBH(OAc)3
MeOH
77d
A solution of 77c (1 eq) and acetone (2 eq) in MeOH (100 uL) was maintained at
rt for 30 min. NaBH(OAc)3 (3 eq) was added and resulting suspension continued stirring
for 30 min. Crude product was concentrated down, then partitioned between EtOAc and
water, the layers were separated and the aqueous layer was extracted with EtOAc (3 X).
The combined organic portions were washed with brine, dried (MgS04), concentrated.
Resulting residue was dissolved in DSMO and purified on semi-prep HPLC to give 77d
as the TFA salt. LCMS m/z 499.1 (MH""), = 2.00 min.
-96-
wo 2005/037273
PCT/US2004/034179
Example 76
Synthesis of N- 1 — [4-( 1 2- f ( 4-fluoro-3 -tetrahvdrofuran-3 -ylphenvDamino] - 1 -methyl- 1 H-
benzimidazol-S -yl } oxy>pyridin-2-yn isopropylglycinamide
Synthesized as described above in Example 75 using 3-(2-fluoro-5-
isothiocyanato-phenyl)-tetrahydro-furan. LCMS m/z 519.2 (MH^), 1.80 min.
Example 77
Synthesis of N-1 — 1 4- [(2- 1 r2-fluoro-5-(trifluoromethyDphenyl] amino } - 1 -methyl- 1 H-
benzimidazol-5-ynQxy]pyridin-2-yU-N-2— isopropylglycinamide
Synthesized as described above in Example 75 using 2-fluoro-5-
trifluoromethylphenyl isothiocyanate. LCMS m/^ 517.3 (MH"^), Rf 2.02 min.
Example 78
Synthesis of N- 1 — [4-( 1 2- [f 4-fluoro-3 -isopropylphenypamino] - 1 -methyl- 1 H-
benzimidazol-5-yUoxy)pyridin-2-yl1-N-2— isopropylglycinamide
Synthesized as described above in Example 75 using 4-fluoro-3-isopropylphenyl
isothiocyanate, LCMS m/z 491.2 (MH""), R^ 2.05 min.
-97-
wo 2005/037273
PCT/US2004/034179
Example 79
Synthesis of N-1 — \4-( (2"rr2-fluoro-5-isopropvlphenvDajiimo]-l-methvl-lH-
benzimidazol-5 -yl } oxy)pyridin-2- yl] — isopropvlgl vcinami de
Synthesized as described above in Example 75 using 2-Fluoro-5-isopropylphenyl
isothiocyanate. LCMS m/z 4912 (M¥t), Rt 2.09 min.
Example 80
S ynthesis of N— 2 — cyclopentyl-N— 1 — {4-(i2- r(4"fluoro- 3 -tetrahydrofur an-3 -
ylphenyPamino] - 1 -methyl- 1 H-benzimidazol-S-yl > oxy)pyridin-2-yl] glycinamide
Synthesized as described above in Example 75 using cyclopropanone and 3-(2-
fluoro-5-isothiocyanato-phenyl)-tetrahydro-furan. LCMS m/z 545.1 (MH^), R/ 2.86 min.
Example 81
Synthesis of l-isopropylazetidin-3-yl 4-|"n-methyl-2-([4-(trifluorQmethyn-
phenyll amino > - 1 H-benzimidazol-5-yl)oxy]pyridin-2-ylcarbamate
-98-
wo 2005/037273
PCT/US2004/034179
Step 1: Synthesis of 3-[4-(4-Methylaimno-3-nitro-phenoxy)-pyridin-2-ylcarb
azetidine- 1 -carboxylic acid tert-butyl ester
83a
1. NEta, DPPA, THF, 0°C
HO,
I
NBOC, toluene, 100 C
83b
"—NBOC
5 To a suspension of acid 1 (1 eq.) in dry THF (10 mL) at 0 °C was added
triethylamine (3.0 eq.) and the resulting reaction was maintained at 0 °C for 45 min to
afford a homogenous solution. Diphenylphosphoryl azide (DPPA, 1.1 eq) was added and
the reaction was maintained o/n allowing the cooling bath to expire. The reaction was
concentrated and the resulting residue dissolved in CH2CI2. The organic portion was
10 washed with saturated NaHCOs (3 X) and the combined aqueous phases were extracted
with CH2CI2. The combined organic portions were dried (MgS04), filtered, and
concentrated. The remaining residue was suspended in toluene. To this suspension was
added A^-BOC azetidin-2-ol (1 eq) and the reaction mixture was heated to and maintained
at 100 °C for Ih. The reaction was then allowed to cool to rt and concentrated. The
15 residue was dissolved in CH2CI2 and washed with saturated Na2C03 (3 X). The
combined aqueous phases were extracted with CH2CI2 and the combined organic layers
were washed with NazCOs and brine, dried (MgS04), and evaporated. The crude residue
was adsorbed onto Si02 and piorified by flash chromatography (9:1,4:1,2:1,1:1
hexanes-EtOAc) to fumish 625 mg (70%) of a light orange solid as 2: IH NMR (300
20 MHz, CDCI3) 5 9.32 (br, s, 1 H), 8.17 (d, J- 6.0 Hz, 1 H), 8.06 (br dd, J- 5.0, 10.2 Hz, 1
H), 7.96 (d, J= 2.8 Hz, 1 H), 7.52 (d, J= 2.5 Hz, 1 H), 7.30 (dd, 7= 2.8, 9.2 Hz, 1 H),
6.93 (d, J= 9.2 Hz, 1 H), 6,57 (dd, J- 2.5, 6.0 Hz, 1 H), 5.18 (dddd, J= 4.4, 4.4, 6.9, 6.9
Hz, 1 H), 4.25 (ddd, J =0.8, 6.9, 10.1 Hz, 2 H), 3.94 (ddd, J = 0.8, 4.4, 10.1 Hz, 2 H),
3.07 (d, J= 5.2 Hz, 3 H), 1.43 (br s, 9 H).
-99-
wo 2005/037273
PCT/US2004/034179
Step 2: Synthesis of 3-[4-(3-Amino-4-methylamino-phenoxy)-pyridin-2-
ylcarbamoyloxy]-azetidine-l-carboxylic acid tert-butyl ester
NBOC
10% Pd/C, MeOH
H2
MeHN
83b
H
1
N O NBOC
83c
A suspension of nitroaniline 83b (1 eq,) in dry MeOH (8 mL) was sparged with
argon over 20 min. 10% Pd/C (0.1 eq) was added in one portion and the reaction vessel
sealed with a three-way stopcock fitted with a balloon filled with hydrogen. The reaction
mixture was purged with hydrogen and the reaction maintained at rt over 3h. The
reaction was filtered through Celite and the filtrate was concentrated to give 474 mg
(94%) of a brown residue as 83c. The material was carried forward without further
purification: LCMS 7n/z 430.3 (MH^), = 2.07 min.
Step 3: l-isopropylazetidin-3-yl 4-[(l-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-lH-
benzimidazol-5-yl)oxy]pyridin-2-ylcarbamate
H2N
MeHN
^l^N O h
F3Q
NCS , DME
NBOC
2. FeCis, pyridine
3. TFA, CH2CI2
4. NaB(OAc)3H. acteone
MeOH
H
/
83c
83d
4-Trifluoromethyl phenylthioisocyanate (1.3 eq.) was added to a solution of
diamine 83c (1 eq.) in dry DME (10 mL) and the reaction was maintained at rt for 14 h.
Pyridine (3 eq.) was added and the reaction cooled to 0 ""C. FeCls (1.2 eq.) was added in
one portion and the resulting reaction was maintained at 0 for 5 min, then at rt for 12
h. The reaction was concentrated and partitioned with EtOAc and saturated Na2C03.
The resulting mixture was filtered through Celite and the remaining solids washed with
EtOAc. The combined phases were then partitioned and separated. The organic phase
was washed with saturated Na2C03 (3 X) and the combined aqueous portions were
extracted with EtOAc, The combined organic portions were washed with brine, dried
(MgS04), and concentrated. The crude residue was adsorbed onto Si02 and purified by
flash chromatography (2 : 1 hexanes-acetone). The resulting material was dissolved in
-100-
wo 2005/037273
PCT/US2004/034179
CH2CI2 (4 mL), treated with TFA (1 mL) and the resulting reaction maintained at rt for 2
h. The reaction was concentrated and partitioned with CH2CI2 and saturated Na2C03.
The organic phase was washed with saturated Na2C03 (3 X) and the combined aqueous
portions were extracted with CH2CI2 (3 X). The combined organic phases were dried
5 (MgS04) and concentrated. The resulting residue was dissolved in MeOH (2 mL) and
treated with an excess of acetone and NaB(OAc)3H. The reaction was maintained at rt
for 14 h and then concentrated. The residue was then suspended in EtOAc and washed
with aqueous 0.5 N HCl solution (3 X). The combined acidic aqueous phases were made
basic (pH = 8) by addition of 1 N NaOH solution. The resulting cloudy aqueous phase
1 0 was extracted with EtOAc (3 X) and the combined organic portions were dried (MgS04)
and concentrated. The resulting residue was further purified by preparative HPLC and
reconstituted as the mono mesylate salt to afford 72 mg of 2 as a white solid: NMR
(300 MHz, CD3OD) 5 8.10 (d, J= 5.9 Hz, 1 H), 7.73 (d, J= 8.9 Hz, 2 H), 7.69 (d, J= 8.9
Hz, 2 H), 7.49 (d, J- 8.7 Hz, 1 H), 7.38 (d, J= 2.2. Hz, 1 H), 7.19 (d, J= 2.2 Hz, 1 H),
15 7.03 (dd, J= 2,2 8.7 Hz, 1 H), 6.65 (dd, J= 2.2, 5.9 Hz, 1 H), 5.19 (m, 1 H), 4.50 (app
dd, J= 6.8, 11.7 Hz, 2 H), 4.24 (app dd, J= 4.9, 11.7 Hz, 2 H), 3.49 (dddd, J= 6,6, 6.6,
6.6, 6.6 Hz, 1 H), 2.69 (s, 3 H), 1.24 (d, J= 6.6 Hz, 6 H); LCMS in/z 541.1 (MH^), =
2.03 min.
Example 82
20 Synthesis of various intermediates for use in the benzimidazole ring formation are
described in this example.
Example 82a. 4-fluoro-3 -cyclopentyl- 1 -nitrobenzene
In a steel pressure vessel with stirbar, sodium acetate (4eq), tetrabutylammonium
25 bromide (1 eq) and Pd(dppf)Cl2-CH2Cl2 (.03 eq) were suspended in DMA
(dimethylacetamide, 0.2M). Nitrogen was bubbled through 10 minutes, then 2-fluoro-l-
iodobenzene (1 eq) and cyclopentene (5eq) were added. The vessel was sealed and heated
at 140^C, 14hrs. The vessel was then cooled to RT, the contents were diluted (ethyl
-101-
wo 2005/037273
PCT/US2004/034179
acetate), washed successively with water (2x), aq. NaHCOs, NaCl, then dried over
anhydrous K2CO35 fihered and stripped to an oil. Chromatography (3%ethyl acetate in
hexaaes on silica gel) provides a pale green oil as a mixture of olefin isomers (83%).
Hydrogenation over palladium on carbon (.5gm 10%w/w) in methaaol (60 mL) at
5 80 psig and RT converts both to a single, volatile alkane 2'fluorophenylcyclopentane.
A solution of 2'fluorophenylcyclopentane in acetic anhydride ( 0.2M) was cooled
to — lO^C. Sulfuric acid (to make l%v/v) was added. Followed by nitric acid (1.15 eq)>
drop wise. After addition was complete, the reaction was allowed to warm to RT. After
30 min at RT, TLC showed complete reaction. The mixture was poured onto ice,
10 extracted into ethyl acetate 2x. The combined extracts were washed successively with
water, aq. NaHCOs, NaCl, then dried over anhydrous K2CO3, filtered and stripped to an
oil. Flash chromatography (3% ethyl acetate in hexanes on silica gel) provides 4-fluoro-3-
cyclopentyl-1 -nitrobenzene (48% yield)
Example 82b. Synthesis of l-tert-butyl-4-fluorobenzene
15 In a steel bomb were combined 4-tert-butyl aniline (leq) and 70% hydrogen
fluoride-pyridine (25g/gm aniline). Sodium nitrite (1.5eq) was then added portion wise
over 5 minutes. The resulting solution was allowed to stir for Ih at room temperature and
then the bomb was sealed and heated at 85°C for Ih. Solution was then quenched with
water/ice and extracted with ethyl ether. Organics washed with brine aad dried with
20 sodium sulfate and concentrated to afford l-tert-butyl-4-fluorobenzene.
NMR (DMSO, 5 ppm): L22(9H, s), 7.07 (2H, t), 7.38 (2H, dd)
Example 82c. Synthesis of 4-tert-butyH-fluoro-2-nitrobenzene
1 -tert-butyl-4-fluorobenzene (leq) was dissolved in concentrated sulfuric acid
(1 .65M) and cooled to O^C in an ice/water bath. Potassium nitrate(leq) was then added in
25 small portions as to allow the temperature of the reaction not to exceed 7^C. After
complete addition the mixture was allowed to stir for aa additional 30 minutes, then
poured onto ice/water and extracted with ethyl acetate. Organics were washed with a
saturated solution of sodium bicarbonate, brine and dried with sodium sulfate and
concentrated. Cmde mixture was purified by flash chromatography on silica.
30 (85%Hex: 1 5%EtOAc) to afford 4-tert-butyH-fluoro-2-nitrobenzene.
^HNMR (CDCI3, 5 ppm): 1.3(9H, s), 7.2(1H, dd), 7.62(1H, ddd), 8.03(1H, dd)
-102-
wo 2005/037273
PCT/US2004/034179
Example 82d. SjTithesis of 5-tert-butyl-2-fluorobenzenamine
To 4-tert-butyl-l-fluoro-2-nitrobenzene in methanol was added a catalytic amount
of palladium on carbon (10%). The mixture was allowed to stir for Ih at room
temperature under an atmosphere of hydrogen. Mixture was filtered though celite and
5 concentrated to afford 5-tert-butyl-2-fluorobenzenamine.
MS:MH^=168
Example 82e. Synthesis of l-(2-fluoro-5-nitrophenyl)ethanone
In a 3 -neck flask equipped with an internal thermometer was added sulfuric acid
and cooled to -10°C in an ice/salt/water batch. 2 -fluoroacetophenone(leq) in sulfuric
10 acid was added drop wise over 10 minutes via addition funnel to produce a solution of
0.2M. Nitric acid (1.15eq) in sulfuric acid was then added dropwise at a rate not to
exceed 5*^C. After complete addition resulting solution was allowed to stir at for 30
minutes. Solution was poured onto ice and extracted with ethyl acetate. Organics were
washed with a saturated solution of sodium bicarbonate, brine, dried with sodimn sulfate
15 and concentrated. Crude product was purified using flash chromatography
(85%Hex:15%EtoAc) on silica to afford l-(2-fluoro-5-nitrophenyl)ethanone.
NMR (CDCI3, 5 ppm): 2.7(3H,s), 7.28(lH,t), 8.4(lH,m), 8.8(lH,dd)
Example 82f. Synthesis of l-fluoro-4-nitro-2-(prop-l-en-2-yl)benzene
KHMDS(leq) in toluene is added dropwise over 5 minutes to a stirred suspension
20 of triphenylphosphinemethyl bromide(L2eq) in THF at — 78^C under nitrogen. After
complete addition solution is allowed to warm to room temperature for 5 minutes then
cooled a second time to -78*^C. l-(2-fluoro-5-nitrophenyl)ethanone(leq) in THF is then
added via cannuUa into the cold suspension over 10 minutes. Resulting mixture is then
allowed to warm to room temperature and stirred for Ih, Solvent is then removed xmder
25 reduced pressure, cyclohexane is then added and mixture heated briefly to reflux, cooled
to room temperature, filtered and filtrate concentrated. Crude product is purified using
flash chromatography(85%Hex:15%EtoAc) on silica to afford l-fluoro-4-nitro-2-(prop-l-
en-2-yl)benzene.
^HNMR (CDCI3. § ppm): 2.15(3H,s), 5.25(2H,d), 7.19(lH,t), 8.1(lH,m), 8.2(lH,dd)
r
-103-
wo 2005/037273
PCT/US2004/034179
Example 82g. Synthesis 2-(2-fluoro-5-iiitrophenyl)-2-methyloxirane
1- fluoro-4-nitro-2- (prop- 1 -en-2-yl) benzene (leq) was dissolved in
dichloromethane and cooled to -lO^C using and ice/salt/water bath under nitrogen.
MCPBA (1.5eq) in dichloromethane was then added dropwise and resulting solution
allowed to warm to room temperature and allowed to stir 48h. Solution was quenched
with 10% sodixmi sulfite, neutralized with saturated solution of sodium bicarbonate,
extracted with dichloromethane. Organics were washed with brine, dried with sodium
stdfate and concentrated. Crude product was purified with flash chromatography
(85%Hex: 15%EtoAc) to afford 2-(2-fluoro-5-nitrophenyl)-2-methyloxirane.
NMR (CDCI3. 5 ppm): 1.7(3H,s), 2.8(1H, d), 3.05(lH,dX 7.2(1H, t), 8.2(lH,m),
8.35(lH,dd)
Example 82h. Synthesis of 2-(2-fluoro-5-nitrophenyl) propanal
2- (2-fluoro-5-nitrophenyl)-2-methyloxirane (leq) was dissolved in ethyl ether
(ImL) xmder nitrogen. BFs-etherate (0,87eq) was added dropwise at room temperature
and after complete addition solution was allowed to stir for Ih. Solution was then
quenched with water, extracted with ethyl ether. Organics washed with brine, dried with
sodium sulfate and concentrated. Crude product was purified using flash chromatography
(85%Hex: 15%EtOAc) on siHca to afford 2-(2-fluoro-5-nitrophenyl) propanal.
^HNMR (CDCI3, 5 ppm): 1.5(3ad), 3.9(lH,c), 7.2(lH,t), 8.15(lH4d), 8.21(iam),
9.7(lH,s)
Example 82i. Synthesis of 2-(2-fluoro-5-nitrophenyl)-2-methylpent-4-enal
To a solution of palladium acetate (O.leq), triphenylphosphine (0.2eq), lithium
chloride (LOeq) in THF were sequentially added 2-(2-fluoro-5-nitrophenyl) propanal
(l.leq) in THF, allyl alcohol (l.Oeq), triethylamine (1.2eq) and triethylborane (2.4eq)
under nitrogen at room temperature. Solution was allowed to stir for 2h. Mixture was
I
diluted with saturated solution of sodium bicarbonate, extracted with ethyl acetate.
Organics were washed with brine, dried with sodium sulfate and concentrated. Crude
product was purified using flash chromatography (85%Hex: 15%EtoAc) on silica to
afford 2-(2-fluoro-5-nitrophenyl)-2-methylpent-4-enal.
^HNMR (CDCI3, S ppm): 1.5(3H, s), 2,6-2.85(2H, m), 5.1(2H,m), 5.5(lH,m), 7.2(lH,t),
8.2(2H,m), 9.7(lH,d)
-104-
wo 2005/037273
PCT/US2004/034179
Example 82j. Synthesis of 2-(2-fluoro-5-nitrophenyl)-2-methylbutaiie-l,4-diol
2-(2-fluoro--5-mtrophenyl)-2-methylpent-4--enal(leq) was dissolved in
dichloromethane:methanol (3:1) and cooled to -78''C. Ozone was then bubbled through
the solution until a blue color was noticed. Air was then passed through the solution
5 followed by the addition of sodixrai borohydride(5eq). Resulting solution was allowed to
warm to room temperature and diluted with brine, extracted with dichloromethane.
Organics were dried with sodium sulfate and concentrated to afford 2-(2-fluoro-5-
nitrophenyl)-2-methylbutane-l,4-diol. The product was used in the next step with no
further characterization.
10 Example 82k. Synthesis of 3-(2-fluoro-5-nitrophenyl)-tetrahydro-3'-methylfuran
To a solution of triphenylphosphine(2eq) in dichloromethane at 0°C under
nitrogen was added dropwise triflic anhydride(leq). After 15 minutes 2-(2-fluoro-5-
nitrophenyl)-2-methylbutane-l,4-diol(leq)was added in dichloromethane followed by
potassium carbonate(leq). The resulting mixture was allowed to warm to room
1 5 temperature for 5h. To the mixture was added water and extracted with dichloromethane.
The organic layer was washed with brme and dried with sodium sulfate and concentrated.
Crude product was purified using flash chromatography (85%Hex:15%EtoAc) on silica
to afford 3-(2-fluoro-5-nitrophenyl)-tetrahydro-3-methylfuran.
NMR (CDCI3, 5 ppm): L45(3H,s), 2.2-2.4(2H,m), 3.85(lH,d). 3.9-4.05(3H,m),
20 7.2(lH,tX 8.15(2H,m)
Example 821. Synthesis of 4-fluoro-3 -(tetrahydro-3 -methylfuran-3 -yl)benzenamine
To 3'-(2-fluoro-5-nitrophenyl)-tetrahydro-3-methylfuran in methanol was added a
catalytic amount of palladium on carbon (10%). The mixture was allowed to stir for Ih at
room temperature under hydrogen atmosphere. Mixture was fdtered though celite and
25 concentrated to afford 4-fluoro-3-(tetrahydro-3-methylfuran-3-yl)benzenamine.
MS:MH^= 196
"105-
wo 2005/037273
PCT/US2004/034179
Example 82m. Preparation of [4-(4-methylamino-3-mtro-phenoxy)-pyridin-2-yl]-
carbamic acid ethyl ester
O2N
MeHN
o
/PrsNEt, CICOsEt
THF, 0 °C
O2N
MeHN
O
O^OEt
Y
N O
Ethyl chloroformate (2 eq.) was added to a stirring solution of aniline 1 (1 eq.)
5 and /Pr2NEt (2 eq.) in dry THF (14 mL) at 0 ""C. The reaction was allowed to warm to rt
over 2 h. The reaction concentrated and the resulting residue dissolved in EtOAc. The
organic phase was washed with saturated aqueous NaHCOa (3 X) and the combined
aqueous portions were extracted with EtOAc. The combined organic portions were
concentrated to give an orange residue as 2. The residue was dissolved in DMF (20 mL),
10 hydrazine monohydrate (1 eq.) added and the resulting reaction maintained at rt for 14 h.
The reaction volume was reduced and the remaining solution was partitioned between
EtOAc and water. The layers were separated and the aqueous phase extracted with
EtOAc (3 X). The combined organic layers were concentrated to give an orange solid as
3 which was carried forward without further purification: LCMS m/z 333.3 (MH^), /r =
15 2.29 min.
Example 82n. Synthesis of 4-(3-aminophenyl)-l-(2,2,2-trifluoroethyl)piperidin-4-ol (3)
CF3
1 3
-106-
wo 2005/037273
PCT/US2004/034179
10
1 equivalent of known compound 1 (WO 9521452) as a IM solution in dry THF
was cooled to — 20°C under argon. 1.1 Eqtiivalents of grignard compound 2 (Aldrich) as a
2M solution in THF was then added dropwise via syringe. Reaction stirred at -20*^C for
20mins, allowed to warm to room temperature, then briefly refluxed.
Solution was then cooled in an ice bath and an excess of dilute aqueous HCl was
carefully added. An aqueous solution of sodium bicarbonate was added to bring the pH
>7 and the product was extracted with ethyl acetate. Removal of organic solvent in vacuo
gave a residue that was purified via silica gel colimm chromatography (30% ethyl acetate
in hexane). Compoxmd 3 was then further purified by recrystallizing from a hexane/ethyl
acetate solution to give a clear oil in a 75% yield. LCMS rn/z 275.3 (MH"^)
Example 82o. Synthesis of 3-[4-Methoxy-l-(2,2,2-trifluoro-ethyl)-piperidin-4-yl]■
phenylamine
i) NaH/DMF
ii) Mel/O^C
OMe
4
To Compound 3 (leq) in dry DMF as a IM solution was added 1.1 eq of sodium
15 hydride at room temperature. This solution was allowed to react for 30mins, The
solution was then cool to O'^C and LI eq of methyl iodine added. Reaction was then
slowly warmed to room temperature where water was added. The product was extracted
with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent
removed to give Compound 4 in sufficient purity. LCMS m/z 289.3 (MH"^).
-107-
wo 2005/037273
PCT/US2004/034179
Example 82p. Synthesis of 3-[l-(2,2,2-Trifluoro-ethyl)-piperidin-4-yl]-phenylamine.
r
CF-
N
OH
i) 6N HCI,
ii) PtO/Ha
EtOH
NH.
r
Compound 3 was heated to 150*^C in a 6N HCI solution via a microwave reactor
for 5mins. Solution was neutralized and extracted with ethyl acetate. After removal of
solvent, the intermediate was dissolved in ethanol and reduced over PtO in a hydrogen
gas atmosphere. The catalyst was removed by filtering through celite and the ethanol
evaporated to give Compoimd 5 .
Example 82q. Synthesis of l-(252,2-Trifluoro-ethyl)-piperidine-4-carboxylic acid [4-(4-
methylamino-3 -nitro-phenoxy)-pyridin-2-yl] -amide
O9N
i) CiaCSOsCCHsCFa)
K^COy acetone , OgN
To 1 eq. of Compound 1 in acetone as a IM solution and 4 eq. Of potassium
carbonate was added leq of 25252-trifluoromethyl trichloromethansulfonate. Solution
briefly reflxoxed, cooled, solvent removed and residue partitioned between water and ethyl
acetate. Organic separated, dried over magnesium sulfate, solvent evaporated to provide
2.
-108-
wo 2005/037273
PCT/US2004/034179
Example 83
Synthesis of N-(4" I [2-(^{ 3 -|"4-fluoro- 1 -f2.2.2-trifluQroet3iYnpiperidm-4-vl]pheiiYU amiuoV
l-methvl-lH-benzirQidazol-5-ynoxv>pvridin-2-vl)acetaxn
85a 85b
Compound 85a (1 eq) was dissolved in dichloromethane to a IM solution under
argon, DAST (Aldrich), 1 eq., was then added and solution allowed to react for Ihr.
Water was added, the phases separated, and the organic solvent removed in vacuo.
The residue was pxirified via silica gel column chromatography (5% MeOH/DCM) to
give Compoimd 85b in nearly quantitative yield. LCMS m/z 557.5 (MH^), 1.61 min.
Examples 84-5 1 5
The compounds in the following Table 1 (Examples 84-515) were similarly
synthesized according to the procedures described in Examples 1-83.
Table 1
Ex.
Structure
Name
84
H3C
H3C
N-[4-({2-[(3-isopropylphenyl)-
amino]-1 -methyl-1 H-benzimidazol-
5-yi}oxy)pyridin-2-yi]acetamide
416.5
85
F
N-[4-({2-[(4-fluorophenyI)amino]-1-
methyl-1 H-benzimidazol-S-
yl}oxy)pyridin-2-yl]acetamide
392.4
86
H,C
N-[4-({2-[(3-ethylphenyl)amino]-1-
methyl-1 H-benzimidazoI-S-
y!}oxy)pyridin-2-y!]acetannide
402.5
-109-
wo 2005/037273
PCT/US2004/034179
oiruvri.iir6
MH-f-
fWII 1 *
87
F
N-{4-[(2-{[2-fluoro-5-(trifluoro
methyl)phenyl]amino}-1-methyl-1H-
benzimidazol-5-yl)oxy]pyriciin-2-
yljacetamide
460.4
88
CH3
H.C
N-[4-({2-[(4-ethyIphenyl)amino]-1-
methyl-1 H-benzimidazol-5-
yl}oxy)pyridin-2-yl]acetamide
402.5
89
F— |— 0
F
N-{4-[(1-methyI-2-{[4-
(trifiuoromethoxy)phenyl]amino}-
1H-benzimidazol-5-y!)oxy]pyridin-2-
yl}acetamide
458.4
90
CH,
H3C
N-[4-({2-[(4-tert-butyiphenyl)amino]-
1 -methyl- 1 H-benzimidazol-5-
yi}oxy)pyridin-2-yI]acetamide
430.5
91
CH3
H3C
N-[4-({2-[(4-isopropyIphenyI)-
amino]-1 -methyI-1 H-benzimidazol-
5-yl}oxy)pyridin-2-yl]acetamide
416.5
92
H3C
N-[4-({2-[(4-chloropheny!)amino]-1-
methyl-1 H-benzimidazoi-5-
yl}oxy)pyridin-2-yI]acetamide
408.9
93
F
H3C
N-{4-[(2-{[4-chloro-3-
(trifiuoromethyI)phenyl]amino}-1-
methyI-1 H-benzimidazol-5-
yl)oxy]pyridin-2-yl}acetamide
476.9
94
CH3
H3C-<.CH3
H3C
N-[4-({2-[(4-isopropyi-3-methyl-
phenyl)amino]-1 -methyl-1 H-
ben2imidazol-5-yi}oxy)pyridin-2-
yl]acetamide
430.5
-no-
wo 2005/037273
PCT/US2004/034179
Structure
Name
IWH+
96
N_[4„({2-[(3-tert-butyI-4-chIoro-
phenyl)amino]-1-methyl-1 H-
benzi m ida2ol-5-yI}oxy ) py rid i n-2-
yl]acetamide
465
96
N-|;4-({2-[(4-chloro-3-thien-2-
ylphenyl)amino]-1-methyl-1 H-
benzimida2ol-5-yl}oxy)pyridin-2-
yfjacetamide
491
97
Br CH3
H3C
N-[4-({2-[(4-bromo-3-methyl-
phenyl)amino]-1 -methyl-1 H-
benzimida2oi-5-yl}oxy)pyndin-2-
yl]acetamide
467.3
98
Br
H3C
N-[4-({2-[(4-bromophenyi)amino]'1-
methyI-1 H-benzimidazol-S-
y l}oxy ) py rid i n-l-yllaceta m Ide
453.3
99
F
H3C
N-{4-[(1-methyl-2-{[4-
{trifluoromethyl)phenyl]amino}-1H-
benzimidazoi-5-yi)oxy]pyridin-2-
yl}acetamide
442.4
100
N-[4-({2-"[(4-chlorophenyl)amino]-1-
methyl-1 H-benzimidazoI-5-
y(}oxy)pyridin-2-yl]piperidine-4-
carboxamide
478
101
H3C
N_[4-({2-[(4-chiorophenyI)amino]-1-
methyl-1 H-benzimidazol-5-
y I}oxy) py rid i n-2-y 1]- 1 -
methylpiperidine-4-carboxamide
492
102
H3G
N-[4-({2-[(4-chlorophenyI)amino]-1-
methyl-1 H-benzimidazol-S-
y|}oxy)pyridin-2-yi]isonicotinamide
471.9
-111-
wo 2005/037273
PCT/US2004/034179
Ex,
Structure
Name
MHhf-
103
CI
H3C
N-[4-({2-[{5-chloro-2-
f luorophenyl)amino]-1 -methyl-l H-
benzimiclazol-5-yl}oxy)pyriciin-2-
yl]acetamide
426.8
104
N-[4-({2-[(5-fluoro-2-methyl-
phenyI)amino]-1 -methyl-1 H-
benzimiciazol-5-yl}oxy)pyridin-2-
yl]acetamide
406.4
105
F
H3C
N-[4'({2-[(2-chloro-5-fIuoro-
phenyi)amino]-1-methyi-1 H-
benzimidazoi-5-yl}oxy)pyndin-2-
yl]aGetamide
426.8
106
H3C
N-[4-({2-[(2-ch!orophenyl)amino]-1-
methyl-1 H-benzimidazol-S-yl}-
oxy)pyridin-2-yl]acetamide
408.9
107
F
H3C
N-[4-({2-[(2,5-difluorophenyl)-
amino]-1 -methyl-1 H-benzimidazoI-
5-yl}oxy)pyridin-2-yl]acetamide
410.4
108
CI
H3C
N-[4-({2-[(2,5-
diclnlorophenyl)amino]-1-methyl-
1H-benzimidazol-5-yl}oxy)pyridin-2-
yl]acetamide
443.3
109
F
H3C
N-{4-[(2-{[2-chloro-5-(trifluoro-
methyl)phenyl]amino}-1 -methyl-1 H-
benzimidazol-5-yl)oxy]pyridin-2-
yi}acetamide
476.9
110
H3C
N-[4-({2-[(2-fluorophenyl)amino]-1-
methyl-1 H-benzimidazoI-5-yl}-
oxy ) py rid i n-2-y I]acetam ide
392.4
-112-
wo 2005/037273
PCT/US2004/034179
Ex.
otruciure
MH+
111
H3C
N-[4-({2-[(3-tert-butylphenyl)amino]-
1-methyl-1 H-benzimidazol-5-
yI}oxy)pyridin-2-y!]-1 -methyl-
piperidine-4-carboxamide
513.7
112
fs|-[4-({2-[(4-fluorophenyl)amino]-1-
methyl"1H"ben2imidazo!-5-yl}oxy)-
pyridin-2-y)]-1 -methylpjperidine-4-
carboxamide
475.5
113
H3C
N-[4-({2-[(3-isopropy!phenyl)-
amino]-1 -methyl-l H-benzimidazoI-
5-yl}oxy)pyridin-2-yl]-1 -
methylpipendine-4-carboxamide
499.6
114
c! >rCH3
H3C
N-[4„({2-[(3-tert-butyI-4-chloro-
phenyl)annino]-1 -methyl-1 H-
ben2imida2oi-5-yI}oxy)pyridin-2-yi]-
1-methylpiperidine-4-carboxamide
548.1
115
F
N-{4-[(1-methyl-2"{[3-(trifluoro-
methyi)phenyi]amino}-1 H-
ben2imida20l-5-y/)oxy]pyridin-2-
yl}acetamide
442.4
116
H3C
H3C
N-[4-({2"[(3-tert-butylphenyl)annino]-
1 -methyl-l H-benzimidazo!-5-yl}-
oxy)pyndin-2-yl]piperidine-4-
carboxamide
499.6
117
F
H3C
N-{4-[(2-{[2-fluoro-5-(trif!uoro-
methyl)phenyi]amino}-1 -methyl-1 H-
ben2imidazo!-5-yl}oxy]pyridin-2-yl}-
1-methylplperidine-4-carboxamide
543.5
118
H3C
H3C
N-[4-({2-[(3-isopropylphenyi)-
amino]-1 -methyl-1 H-benzimidazol-
5-yl}oxy)pyridin-2-yllp(pend(ne-4-
carboxamide
485.6
-113-
wo 2005/037273
PCT/US2004/034179
ex*
Name
l\/IH+
119
H3C
N-[4-({2-[(3-tert-buty!-4-chloro-
pheny[)amino]-1 -methyM H-
ben2imiciazol-6-yl}oxy)pyridin-2-
yl]piperidin6-4-carboxamide
534.1
120
N-[4-({2-[(4-chloro-3-isopropyi"
phenyI)annino]-1 -methyl-1 H-
benzimidazol-6-yl}oxy)pyridin-2-
yl]piperidine-4-carboxamide
520
121
F
N-{4-[{ 1 -methy l-2-{[4-(trif luoro-
methyl)phenyI)amino}-1 H-
ben2imidazol-5-yl)oxylpyridin-2-
yi}piperidine--4-carboxamide
511.5
122
H3C
N-{4-[(2-{[4-chloro-3-(trifluoro-
methyi)phenyI]amino}-1 -nnethy!-1 H-
benzimidazo!-5-yI)oxy]pyridin-2-
yi}piperidine-4-carboxamide
546
123
H3C
N-{4-[(2-{[3-chloro-4-(trifluoro-
methyi)pheny!]amino}-1-methyI-1H-
benzimidazol-6-yl)oxy]pyridin-2-
y}}piperidine-4-carboxamide
546
124
VCH3 CH,
N-[4-({2-[(3-tert-butyIphenyl)amino]'-
1 -methyl-1 H-benzimidazol-5-y 1}-
oxy)py ridin-2-yl]-1 -isopropy i-
piper id i ne-4-carboxam ide
541.7
125
N-[4-({2-[(3-tert-butylphenyl)amino>
1-methyl-1 H-benzimidazol-5-
yl}oxy)pyridin-2-yll-1 -ethyl-
piperidine-4-carboxamide
527.7
126
H3G
H3C
1 -ethyl"N-[4-({2-[(3-isopropyl-
phenyl)amino]-1 -methyl-1 H-
benzimidazoi-5-yl}oxy)pyridin-2-
yl]piperidine-4-carboxamide
513.7
-114-
wo 2005/037273
PCT/US2004/034179
Ex.
Structure
Name
MH+
127
1 -ethyI-N-[4-({2-[(4-fluoro-3-
isopropylphenyI)amino]-1-methyl-
1H-benzimidazol-5-yi}oxy)pyridin-2-
yl]piperidine-4-Garboxamide
531.6
128
H3C
H3C
N-[4-({2-[(4-chloro-3-isopropyi-
phenyl)amino]-1 -methyI-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yi]-
1 -ethyIpiperidine-4-carboxamide
548.1
129
H3CCH3
H3C
N-[4-({2-[(3-tert-butyl-4-chIoro-
pheny!)amino]-1 -methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-y!]-
1 -ethylpipendine-4-carboxamide
562.1
130
F
1-ethyl-N-{4-[(1-methyl-2-{[4-
(trifluoromethyl)phenyl]amino}-1H-
benzimidazoI-5-yi)oxy]pyridin-2-
yl}piperidine-4-carboxamide
539.6
131
F F
Ct V-F
H3C
N-{4-[(2-{[4-chioro-3-(trifluoro-
nnethyI)phenyl]amino}-1-methy!-1H-
benzimidazol-5-yl)oxy]pyridin-2-yl}-
1-ethyipiperidine-4-carboxamide
574
132
H3C
^J^CHg CH3
1-isopropyl-N-[4-({2-[(3-isopropyl-
phenyl)amino]-1 -methyI-1 H-
benzimidazol-5-yl}oxy)pyridin-2-
yI]piperidine-4-carboxamide
527.7
133
H3C
N-[4-({2-[(4-fIuorO'-3-isopropyI-
phenyl)amino]-1 -methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
1-isopropylpiperidine-4-
carboxamide
545.7
134
CI )— CH3 CH3
H3C
N-[4-({2-[(4-chloro-3-isopropyl-
phenyI)amino]-1-methyl-1H-
benzimidazol-5-yl}oxy)pyridin-2-yi]-
1 -isopropylpiperidine-4-
carboxamide
562.1
-115-
wo 2005/037273
PCT/US2004/034179
ex.
otructure
Name
lvin+
135
CH3
N-[4-({2-[(3-tert-butyl-4-chloro-
phenyl)amino]-1 -methyl-l H-
benzimiciazo!"5-y!}oxy)pyridin-2-yl]-
1 '■isopropylpiperidine-4-
carboxamide
576.2
136
F
N-{4-[(2-{[3-chioro-4-(trifluoro-
methyI)phenyl]amino}-1-methyl-1H-
ben2imida2ol-5-yl)oxy]pyridin'-2-yl}-
1 -ethylpiperidine-4-carboxamide
674
137
H3C
H3C
N-[4-({2-[(3-isopropy!phenyl)-
amrno]-1-methyl*1 H-benzimidazol-
5-yi}oxy)pyridin-2-yI]-3-piperidin-4-
ylpropanamide
613.7
138
H3CCH3
H3C
N'-[4-({2'-[(3-tert-butylphenyl)amino]-
1 -methyl-1 H-benzimidazol-S-
y l}oxy ) py rid in-2-y i]-3-piperid i n-4-
ylpropanamide
527.7
139
H3C
F >-CH3
N-[4-({2-[(4-fiuoro-3-isopropyl-
phenyi)amino]-1 -methyi-1 H-
benzimidazol-5-y!}oxy)pyridin-2-yl]-
3-piperidin-4-ylpropanamide
531.6
140
CI,^V-CH3
H3C
N-[4-({2-[(4-ch!oro-3-isopropy(-
phenyl)amrno]-1-methyl-1H-
benzimida20l~5-yl}oxy)pyridin-2-yl]-
3-pipendin-4-ylpropanamide
548.1
141
N-[4-({2-I(3-tert-butyl-4-chloro-
phenyl)amino]-1 -methyl-l H-
benzimida2ol-5-yi}oxy)pyridin-2-yl]-
3-piperidin-4-ylpropanamide
562.1
142
F f
H3C
N-{4^[(2-{[4-chloro-3-(trifluoro-
methyl)phenyI]amino}-1 -methyl-1 H-
ben2imida2ol-5-yl)oxy]pyridin-2-yl}-
3-piperidin-4-yipropanamide
574
-116-
wo 2005/037273
PCT/US2004/034179
Ex
Structure
MH+
143
N-{4-[(2-{[4-chloro-3"(trifIuoro-
nnethyl)phenyl]amino}-1 -methyl-1 H-
benzimiclazol-5-yl)oxy]pyridin-2-yl}-
1-methyIpiperidine-4-carboxamide
560
144
F
F--f-f^ CI
N-{4-[(2'-{[3"Chloro-4-(trifluoro-
methyl)phenyl]amino}-1 -methyi-1 H-
benzimidazol-5-yl)oxy]pyridin-2-yl}-
l-methylpiperidine-4-carboxamide
560
145
N-[4-({2-I(4-ethyiphenyI)amino]-1-
methyi-1H-benzimidazoi-5-yi}oxy)-
pyridin-2-yI]-1-methylpiperidine-4-
carboxamide
485.6
146
F
H3C
N-{4-[(2-{[4-fluoro-3-(trifluoro-
methyI)phenyl]aiTiino}-1-methyI-1H-
benzimidazol-5-yl)oxy]pyridin-2-yl}-
1-methylpiperidine-4-carboxamide
543.5
147
H3C CH,
H3C
N-[4-({2-[(3-tert-buty!phenyl)anriino]-
1 -methyl-1 H-benzimidazol-5-
yl}oxy)pyridin-2-yI]-3-(1-methyI-
piperidin-4-yi)propanamide
541.7
148
N-[4-({2-[(3-isopropyIphenyl)-
annino]-1 -methyl-1 H-benzimidazoi-
5-yl}oxy)pyridin-2-yI]-3-(1-methyl-
piperidin-4-yi)propanamide
527.7
149
N-[4-({2-[(4-fluoro-3-isopropyl-
phenyl)amino]'-1 -methyI-1 H-
benzimidazo!-5-yi}oxy)pyridin-2-yl]-
3-(1-methylpiperidin-4-
yl)propanamide
545.7
150
N-[4-({2-[{4-chloro-3-isopropyI-
phenyOaminoJ-l -methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
3-(1-methyIpiperidin-4-yl)-
propanamide
562.1
-117-
wo 2005/037273
PCT/US2004/034179
otructure
iMaine
IVjn+
151
N.[4-.({2-[(3-tert-butyi-4-chloro-
phenyI)amino]-1-methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
3-(1-methylpiperidin-4-yl)-
propanamide
576.2
152
CI V-F
H3C
N-{4-[(2-{[4-chloro-3-(trifluoro^
methyI)phenyl]amino}-1 -methyl-1 H-
benzimidazol-'5-yI)oxy]pyridin'-2-yl}-
3-(1-methylpiperidin-4-yl)-
propanamide
1 1
588
153
H3CCH3
_/-CH3
H3C
N-[4-({2-[(3-tert-butyIphenyl)amino]-
1 -methyl-1 H-benzimidazol-5-yI}-
oxy)pyndin-2-yl]-1-(2-methoxy-
ethyl)pipendine-4-carboxamide
557.7
154
H3C
__>-CH3
H3C
N-[4-({2-[(3-isopropylphenyl)-
amino]-1 -methyl-1 H-ben2imida2ol-
5-yl}oxy)py^idin-2-yl]-1-(2-methoxy-
ethyl)piperidine-4-carboxamide
543.7
155
H3C
H3C
N-[4-({2-[(4-fluoro-3-isopropyl-
phenyl)am[no]-1-methyI-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
1 -(2-methoxyethyI)piperidine-4-
carboxamide
561.7
156
H3C
N-[4-({2-[(4-chloro-3-isopropyl-
pheny l)amino]-1 -methyl-1 H-
benzimidazoi-5-yl}oxy)pyridin-2-yl]-
1-(2-methoxyethyI)piperidlne-4-
carboxamide
578.1
157
N-[4-({2-[(3-tert-butyl-4-chloro-
phenyI)amino]-1 -methyl-1 H-
benzimidazoi-5-yI}oxy)pyridin"2-yI]-
1-(2-methoxyethyi)piperidine-4-
carboxamide
592.2
158
H3C
N-{4-[(2-{[4-chloro-3-(trifiuoro-
methyl)phenyl]amino}-1 -methyI-1 H-
benzimidazol-5-yi)oxy]pyridin-2-yl}-
1 -(2-methoxyethyI)pipendine-4-
carboxamide
604
-118-
wo 2005/037273
PCT/US2004/034179
Ex.
Structure
Name
MH+
159
H3C CH3
N-[4-({2-[(3-tert-butyI-4-ch!oro-
phenyI)amino]-1 -methyl-l H-
ben2imidazol-5-yl}oxy)pyricIin-2-yl]-
1 -(2-hydroxyethyl)piperidine-4-
carboxamide
578.1
160
N-[4-({2-[(3-tert-butylphenyI)amino]-
1-methyl-1 H-benzimidazoi-5-yl}-
oxy)pyndin-2-yl]-4-morpholin-4-
ylbutanamide
543.7
161
HgC
N-[4-({2-[(3-isopropylphenyl)-
amino]-1 -methyl-1 H-benzimidazol-
5-yI}oxy)pyridin-2-yl]-4-morpholin-
4-ylbutanamide
529.7
162
H3C
H3C
N-[4-({2-[(4-fluoro-3-isopropyI-
phenyi)amino]-1 -methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
4-morpholin-4-yIbutanamide
547.6
163
H3C
N-[4-({2-[(4-chioro-3-isopropyl-
phenyf)amino]-1 -methyi-1 H-
benzinnidazol-5-yI}oxy)pyridin-2-yl]-
4-morpholin-4-ylbutanamide
564.1
164
H3C CH3
N'-[4-({2-[(3-tert-butyl-4-chloro-
phenyl)amino]-1 -methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
4-morpholin-4-ylbutanamide
678.1
165
N-[4-({2-[(3-tert-butylphenyi)amino]-
1 -methyM H-benzimidazol-6-
y l}oxy) py rid in -2-y 1]- 1 -(2-h y d roxy-
ethyl)piperidine-4-carboxamide
543.7
166
H3C
N-[4-({2-[(4-fluoro-3-isopropyI-
phenyl)amino]-1 -methyl-l H-
benzimldazol-5-yl}oxy)pyridin-2-yl]-
1 -(2-hydroxyethyl)piperidine-4-
carboxamide
547.6
-119-
wo 2005/037273
PCT/US2004/034179
niotiir^
Nam6
1 veil ■ 1 w
MH+
■■■■ 1 *
167
N-[4-({2-[(3-isopropylphenyl)-
amino]-1 -methyl-1 H-benzimldazoI-
5-yl}oxy)pyridin-2-yl]-3-(1-isopropyl-
piperidin-4-yl)propanamide
555.7
168
KjC
N-[4-({2-[(3-tert-butyl-4-chloro-
phenyi)amino]-1 -methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
3-( 1 -isopropylpiperidin-4-yl)-
propanamide
604.2
169
H3C
X^A ^^^^
H N-"^'^ 0 CH3
N^1^-[4-({2-[(3"tert-butylphenyl)-
amino]-1-methyl-1H-benzimidazol-
5-y l}oxy ) py rid i n-2-y !]-N "-2^-methy 1-
glycinamide
459.6
170
H3C
H3C
fsl^-t— .[4_({2-[(4-fluoro-3-isopropyI-
phenyI)amino]-1 -methyI-1 H-
benzimidazol-5-yI}oxy)pyridin-2-yl]-
lsi^2'-'-methylglycinannide
463.5
171
H3C
>-CH3
H3C
N'^1'— [4-({2-[(2-fluoro-5-isopropyI-
phenyl)amino]-1 -methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yi]-
N^2'-'-methylglycinamide
463.5
172
F
H3C
N^2'--methyl-N'-1 — {4-[(1 -methyI-2-
{[4-(trifiuoromethyi)phenyl]amino}-
1H-benzimidazol-6-yl)oxy]pyridin-2-
yl}glycinamide
471.5
173
1 -isopropy l-N-{4-[( 1 -methy l-2-{[4-
(trifluoromethyl)phenyl]amino}-1H-
benzimidazol-5-yI)oxy]pyridin-2-
yl}piper]dine-4-carboxamide
553.6
174
F
H^N-Jl^ H^N 0 k^N CH,
H3C CH3
N-[4-({2-[(2 , 5-dif 1 uorophen yl)-
amino]-1 -methyl-1 H-benzimidazol-
5-yl}oxy)pyridln-2-yl]-2-(4-isopropyl-
piperazin-1-yl)acetamide
536.6
-120-
wo 2005/037273
PCT/US2004/034179
ex.
oiruciure
iM3me
nnrl+
175
F
H3C CH3
2-(4-isopropyIpiperazin-1-yl)-N-{4-
[(1-methyl-2-{[3-(trifluoromethyI)-
phenyl]amino}-1H-benzimidazol-6-
yI)oxy]pyridin-2-yl}acetamide
568.6
176
H3C CH3
N-{4-[(2-{[2-chloro-5-(trifluoro-
methyI)phenyl]amino}-1 -methyl-1 H-
benzimidazol-5-yl)oxy]pyridin-2-yl}-
2-(4-isopropylpiperazin-1 -
yl)acetamide
603.1
177
N-[4-({2-[(2-fluorophenyl)ainino]-1-
methyl-1H-benzimidazol-5-yl}oxy)-
pyridin-2-yl]-2-(4-isopropyI-
piperazin-1 -yl)acetamide
518.6
178
F
h"^N-^U^ 0 CH3
H3C
N-2--methyI-N-1 '-{4-[(1 -methyl-2-
{[3-(trifluoromethyI)phenyl]amino}-
1H-benzimidazol-5-yl)oxy]pyridin-2-
yl}giycinam[de
471.5
179
H^C ^'^a
N-{4-[{2-{[2-fIuoro-5-(trifluoro-
methyI)phenyl]amino}-1 -methyl-1 H-
benzimidazoI-5-yl)oxy]pyridin-2-yl}-
2-[4-(2-methoxyethyl)piperazin-1-
yilacetamide
602.6
180
F
N-{4-[(2-{[2-chloro-5-(trifluoro-
methyl)phenyl]amino}-1 -methyI-1 H-
benzimidazol-5-yl)oxy]pyridin-2-yI}-
2-(4-ethy[piperazin-1-yl)acetamicie
589
181
F
H3C "^^3
N-{4-[(2-{[2-chloro-5-(trifluoro-
methyI)phenyl]amino}-1 -methyI-1 H-
benzimidazol-5-yl)oxy]pyr]din-2-yj}-
2-[4-(2-methoxyethyI)piperazin-1-
yljacetamide
619.1
182
F
N-{4-[(2-{[2-chIoro-5-{trifluoro-
methyl)phenyi]amino}-1 -methyl-1 H-
benzimidazol-5-yI)oxy]pyridin-2-yl}-
2-[4-(2-hydroxyethyl)piperazin-1-
yl]acetamide
605
-121-
wo 2005/037273
PCT/US2004/034179
Fx
Kl -a tni^
MM4-
183
N-{4-[(2-{[2-chioro-5-(trifluoro-
methyl)phenyl]amino}-1-methyI-1H-
ben2imidazol-5-yl)oxy]pyridin-2-yl}-
1 -(2-methoxyethyI)piperidine-4-
carboxamide
604
184
H3C
N-[4-({2-[(3-isopropylphenyi)-
amino]-1 -methyl-1 H-benzimidazol-
5-y l}oxy ) py rid in-2-y l]-2-(4-
methylpiperazin-1 -yl)acetamide
514.6
185
N-[4-({2-I{3-tert-butylphenyl)amino]-
1 -methyl-1 H-benzimidazoi-6-
yl}oxy)pyridin-2-yi]-2-(4-methyl-
piperazin-1 -yl)acetamide
528.7
186
N-[4-({2-[(4-chIoro-3-isopropyl-
phenyi)amino]-1 -methyi-1 H-
benzimidazo!-5-y!}oxy)pyridin-2-yl]-
2-(4-methylpiperazin-1 -
yl)acetamide
549.1
187
H3C CH3
N-[4-({2-[(3-tert-butyI-4-chloro-
phenyl)amino]-1 -methyl-1 H-
ben2imidazol-5-yi}oxy)pyridin-2-yl]-
2-(4-methylpipera2in-1 -
yi)acetamide
563.1
188
H3C
H3C
N-[4-({2-[(4-fluoro-3-isopropyl-
phenyl)amino]-1 -methyi-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
2-(4-methylpipera2in-1 -
yl)acetamide
532.6
189
F F
2-(4-methyipiperazin-1 -yi)-N-{4-[( 1 -
methyl-2-{[3-(trifluoromethyl)-
phenyl]amino}-1H-benzimidazol-5-
yi)oxy]pyridin-2-yl}acetamide
540.6
190
H3C
H3C
N-[4-({2-[(3-lsopropylphenyl)-
amino]-1 -methyl-1 H-benzimidazol-
5-yI}oxy)pyridin-2-yl]'-2-pyrrolidin-1-
ylacetamide
485.6
-122-
wo 2005/037273
PCT/US2004/034179
Ex.
Structure
Name
MH+
191
H3C
N-[4-({2-[(4-fluoro-3-isopropyl-
phenyl)amino]-1-methyl-1 H-
benzinniciazol-5-yi}oxy)pyriciin-2-yl]-
2-pyrrolidin-1-ylacetamide
503,6
192
H3C CH3
ci^^y-cH3
H3C
N-[4-({2'-[(3-tert-butyl-4-chloro-
phenyl)amino]-1-methyl-1H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
2-pyrrolidin-1-yIacetamide
534.1
193
F F
H3C
N-{4-[(2-{I2-fluoro-5-(trifluoro-
methyi)phenyi]amino}-1-methyl-1H-
benzimidazol-6-yl)oxy]pyridin-2-yl}-
2-pyrroIidin-1-ylacetamide
529.5
194
H3C
H3C
N-[4-({2-[(4-chloro-3-isopropy!-
phenyl)amino]-1 -methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
2-pyrroIidin-1 -ylacetamide
520
195
H3C CH3
H3C
N-[4-({2-[{3-tert-butylphenyl)amino]-
1 -methyl-1 H-benzimidazol-5-
yl}oxy)pyridin-2-yl]-2'-pyrrolidin-1-
ylacetamide
499.6
196
H3C Chtrat
2-[(2R,6S)-2,6-dimethylmorpho![n-
4-yl]-N-[4-({2-[(3-isopropyI-
pheny!)amino]-1-methyi-1 H-
benzimidazol-5-yl}oxy)pyridin-2-
yl]acetamide
529.7
197
H3C CH3 ' Chfral
N-[4-({2-[(3-tert-butylphenyl)amino]-
1-methyi-1 H-benzimidazoI-S-
yI}oxy)pyridin-2-y!]-2-[(2R,6S)"2,6-
dirTiethylmorphoIin-4-yl]acetannide
543.7
198
2-[(2R,6S)-2,6-dimethyImorphoIin-
4-y|]-N-{4-[(2-{[2-fluoro-5-
(trifluoromethy!)phenyi]amino}-1-
methyl-1 H-benzlmidazol-5-
yl)oxy]pyridin-2-yl}acetamide
573.6
-123-
wo 2005/037273
PCT/US2004/034179
Ex
S^triictiire
111 UWLUI ^
NaiTi6
MH+
199
H3C Chrra]
HaC CH3
2-[(3R,5S)-3,5-ciimethylpipera2in-1-
yll-N-[4K{2-[(3-isopropyl-
phenyl)amino]-1-methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-
yl]acetamide
528.7
200
H3C CHg
2-[(3R,6S)-3,5-dimethylpiperazin'1-
yl]-N-[4-({2-I(4-fluoro-3-isopropyl-'
phenyi)amino]-1 -methyl-1 H-
ben2imidazoi-5-yl}oxy)pyridin-2-
yl]acetamide
546.7
201
H3C Chira!
HgC CH3
2-[(2R,6S)-2,6-dimethy!morphoiin-
4-yl]-N-[4-({2-[(4-fIuoro-3-isopropyl-
phenyi)amino]-1 -methyl-1 H-
ben2imidazol-5-yl}oxy)pyridin-2-
yl]acetamide
547.6
202
H3C Chiral
N-[4-({2-[(4-chioro-3-isopropyl-
phenyl)amino]-1 -methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yI]-
2-[(2R,6S)-2,6-dimethylmorpholin-
4-yl]acetamide
564.1
203
2-(3-hydroxyazetidin-1-yl)-N-[4-({2-
[(3-isopropyiphenyl)amino]-1 -
methyl-1 H-benzimidazoi-5-yi}-
oxy ) py r i d i n -2-y 1 ]aceta m ide
487.6
204
fJVch3
H3C H
N-[4-({2-[(4-fluoro-3-isopropyl-
phenyl)amino]-1 -methyl-1 H-
benzimidazol-5-y!}oxy)pyridin-2-yl]-
2-(3-hydroxyazetidin-1-yl)-
acetamide
505.6
205
H3C
H3C
N-[4-({2-[(3-isopropylphenyl)-
amino]-1-methy!-1H-ben2imidazol-
5-yl}oxy)pyridin-2-yi]-'2-piperazin-1-
ylacetamide
500.6
206
H3C
H3C
N-[4-({2-[(4-fluoro-3-lsopropyl-
phenyl)amino]-1 -methyl-1 H-
benzimida20l-5-yl}oxy)pyridin-2-yl]-
2-piperazin-1 -ylacetamide
518.6
-124-
wo 2005/037273
PCT/US2004/034179
207
N-[4-{{2-{{4-chioro-3-isopropyl-
phenyi)amino]-1 -methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
2-pipera2in-1 -yiacetamide
535.1
208
H3C
N-[4-({2-[(3-tert-butylphenyi)amino]-
1 -methyl-1 H-benzimidazo!-5-y!}-
oxy)pyridin-2-yl]-2-piperazin-1-
yiacetamide
514.6
209
H3C CH3
N-[4-({2-[{3-tert-butyl-4-chloro-
phenyl)amino]-1 -methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
2-piperazin-1 -yiacetamide
549.1
210
H3C
H-C
N-[4-({2-[(3-isopropylphenyi)-
aminD]-1 -methyl-1 H-benzrm^dazoi-
5-y!}oxy)pyridin-2-yl]-2-'piperidin-1-
ylacetamide
499,6
211
H3C
N-[4-({2-[(4-fluoro-3-isopropy(-
phenyI)amino]-1 -methyl-1 H-
benzimidazol-5''yl}oxy)pyridin-2-yi]-
2-piperidin-1 -yiacetamide
517.6
212
H3C
H3C
N-[4-({24{4-chIoro-3-isopropyl-
phenyl)amino]-1-methyi-1 H-
benzlmidazol-5-y[}oxy)pyridin-2-yl]-
2-piperidin-1 -yiacetamide
534.1
213
H3C
N-[4-({2-[(3-tert-butyiphenyi)amino]-
1 -methyl-1 H-benzimidazol-S-yl}-
oxy)pyridin-2-yi]-2-pipendin-1 -
yiacetamide
_~ — . — ^ ■ .> —
513.7
1
214
N-[4-({2-[(3-isopropylphenyl)-
amino]-1 -methyl-1 H-benzimidazol-
5-yl}oxy)pyridin-2-yl]-2-(4-isopropyI-
piperazin-1 -yl)acetamide
542.7
-125-
wo 2005/037273
PCT/US2004/034179
Ex.
Structure
Name
MH+
215
H3C
H3C CH3
N-[4-({2-[(4-fluoro-3-isopropyl-
phenyI)amino]-1-methyl-1H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
2-(4-isopropyIpiperazin-1-yl)-
acetamide
560.7
216
V13C
H3C CH3
N-[4-({2-[(4-chloro-3-isopropyl-
phenyl)amino]-1 -methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yi]-
2-(4-isopropylpiperazin-1-
yl)acetamide
577.1
217
H3C CH
H3C CHj
N-[4-({2"[{3-tert-butyIphenyl)amino]-
1 -methyl-1 H-benzimidazol-5-yi}-
oxy)pyridin-2-yl]-2-(4-isopropyl-
piperazin-1-yl)acetamide
556.7
218
H3C CH
CJ "y-CH3
H3C CH3
N-I4-({2-[(3-tert-butyl-4-chloro-
phenyl)amino}-1 -methyl-1 H-
benzimidazol-5-yi}oxy)pyridin-2-yl]-
2-(4-isopropylpipera2in-1-yl)-
acetamide
591.2
219
H3C
N-{4-[(2-{[2-fluoro-5-(trifiuoro-
methyl)phenyi]amino}-1 -methyl-1 H-
benzimidazoI-5-yl)oxy]pyridin-2-yI}-
2-(4-isopropylpiperazin-1-
yl)acetamide
586.6
220
H3C CH3
N-{4-[(2-{[3-chloro-4-(trifluoro-
methyl)phenyl]amino}-1 -methyl-1 H-
benzimidazol-5-yl)oxy]pyridin-2-yl}-
2-(4-lsopropyipiperazln-1 -yl)-
acetamide
603.1
221
H3C
2-(4-ethyipiperazin-1-yi)-N-[4-({2-
[(3-isopropylphenyl)amino]-1 -
methyl-1 H-benzimidazol-5-yl}-
oxy)pyridin-2-yl]acetamide
528.7
222
H3C
CI ">-CH3
N-[4-({2-[(4-chloro-3-isopropyl-
phenyl)amino]-1 -methyl-1 H-
ben2imldazol-5-yl}oxy)pyridin-2-yi]-
2-(4-ethylpiperazin-1-yi)acetamide
563.1
-126-
wo 2005/037273
PCT/US2004/034179
Ex.
223
224
225
226
227
228
Structure
CH,
,CH,
H3C
F F
F-V CI
H
H3C
CH,
-CH,
H3C
CI
H3C.
CH,
H3C
H3C
CH,
H
H3C
Name
N-[4-({2-[(3-tert-butylphenyl)amino]-
1-methyl-1 H-benzimidazol-S-yl}-
oxy)pyridin-2-yl]-2-(4-ethy!-
piperazin-1 -yl)acetamicle
N-{4-[(2-{[3-chloro-4-(trifluoro-
methyl)phenyl]amino}-1-methyl-1H-
benzimidazol-5-yI)oxy]pyriciin-2-yI}-
2-(4-ethylpiperazin-1-yl)acetamide
2-(4-ethylpiperazin-1-yi)-N-[4-({2-
[(4-fluoro-3-isopropylphenyl)-
amino]-1 -methyl-1 H-benzimidazoi-
5-yl}oxy)pyridin-2-yl]acetamide
N-[4-({2-[(3-tert-butyl-4-chloro-
phenyl)amino]-1 -methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
2-{4"ethylpiperazin-1-y[)acetannide
N-[4-({2-[(3-isopropylphenyl)-
amino]"1 -methyi-1 H-benzimidazoI-
5-yl}oxy)pyridin-2-yi]-2-morpholin-
4-ylacetamide
|si-.[4-({2-[(4-fiuoro-3-isopropyl-
phenyl)amino]-1 -methyl-1 H-
benzimidazol-5-yI}oxy)pyridin-2-y!]-
2-morpholin-4-yiacetamide
MH+
542.7
589
546.7
577.1
501.6
519.6
229
230
H3C
Ct V-CH,
H
H3C
N-[4-({2-[(4-chloro-3-isopropyj-
phenyl)amino]-1-methy[-1H-
benzimidazol-5-yI}oxy)pyridin-2-yl]'-
2-morpholin-4-y!acetamide
CH,
536
H3C
N-[4-({2-[(3-tert-butylphenyl)amino]-
1 -methyl-1 H-benzimidazol-5-yl}-
oxy)pyridin-2-yl]-2-morphoIin-4-
ylacetamide
615.6
-127-
wo 2005/037273
PCT/US2004/034179
ex.
iwiriT
231
H3C CH3
H3C
N-[4-({2-[(3-tert"butyl-4-chloro-
phenyf)amino]-1-nnethyf-1 H-
ben2lmida2ol-5-yl}oxy)pyrid(n-2-yl]-
2-morpholin-4-yIacetamide
550.1
232
F F
H3C
N-{4-[(2-{[2-fluoro-5-(trifluoro-
methyl)phenyl]amino}-1 -methyl-1 H-
benzimidazoI-5-yl)oxy]pyridin-2-yI}-
2-morpholin-4-ylacetamide
545.5
233
F F CbltaO
2-[(2R,6S)-2,6-dimethylmorpholin-
4-yi]-N-{4-[( 1 -methyl-2^{{4-{trifluoro-
methyl)phenyI]amino}-1 H-
ben2imidazol-5-yl)oxy]pyndin-2-
yl}acetamide
555.6
234
F F
2"[(2R,6S)-2,6-dimethyImorpholin-
4-yf]-N-{4-[(1-methyl-2-{[4-
{tnfluoromethoxy)pheny\]amlno}-
1H-benziniidazol-5-yl)oxy]pyndjn-2-
yl}acetamide
571.6
235
H3C
2-a2etidin-1-y!-N^[4-({2-[(4-fluoro-3-
isopropylphenyl)amino]-1-methyl-
1H-ben2imida2ol-5-yl}oxy)pyndin-2-
yljacetamide
489.6
236
H3C
2-a2etidin-1"yl-N-I4-({2-[(34ert-
butylphenyl)amrno]-1 -methyl-1 H-
benzinnida2ol-5-yi}oxy)pyridin-2-
yljacetamide
485,6
237
F F
2-azetidin-1-yi-N-{4-[(2-{[2-fiuoro-5-
(tnf}uoromethy\)pheny\]am\no}--1''
methyl-1 H-benzimidazol-5-yi)-
oxy]pyridin-2-yl}acetamide
515.5
238
H3C
2-azetidin-1-yI-N-I4-({2-[(2-fluoro-6-
isopropylphenyl)amino]-1-methyl-
1H-benzimida2ol-5-yI}oxy)pyridin-2-
y[]acetamide
489.6
-128-
wo 2005/037273
PCT/US2004/034179
Ex
Striip^tiir©
will UWtiUI w
Name
MH+
IWl 1 1 *
239
0
H,C
2-azetidin-1-yl"N-{4-[(1-methyl-2-
{[4-(trifluoromethoxy)phenyl]-
amino}-1 H-benzimidazol-S-yl)-
oxy]pyricIin-2-yl}acetamide
513.5
240
H3C
H3C
N-[4-({2-[(2-f!uoro-6-isopropyl-
phenyI)amlno]-1 -methyi-1 H-
ben2imidazol-5-yl}oxy)pyridin-2-yl]-
2-pyrrolidin-1-ylacetamide
503.6
241
F F
H3C
N-{4-[(1-methyl-2-{[4-(trifluoro-
methyl)phenyl]annino}-1 H-
ben2imida2ol-5-yl)oxy]pyridin-2-yl}-
2-pyrrolidin-1-ylacetamide
511.5
242
F F
0
N-{4-[(1-methyl-2-{[4-(trifluoro-
nnethoxy)phenyl]amino}-1 H-
benzimidazol-5-yl)oxy]pyridin-2-yi}-
2-pyrroIidin-1-ylacetamide
527.5
243
F F
2-(4-isopropyipiperazin-1-yl)-N-{4-
[(1-methyl-2-{[4-(trifIuoromethyi)-
phenyl]amino}-1H-benzimida2oi-5-
y!)oxy]pyridin-2-yl}acetamide
568.6
244
F F
^X-F
2-(4-isopropyipiperazin-1-yl)-N-{4-
[(1-methyl-2-{[4-(trifluoromethoxy)-
phenyl]amino}-1H-benzimida20i-5-
yl)oxy]pyridin-2-yl}acetannide
584.6
245
F F
N_{4_[(2-{[2-fluoro-5-(trifluoro-
methyl)phenyf]amino}-1-methyl-1H-
benzimidazoI-5-yl)oxy]pyridin-2-yl}-
2-(4-nnethylpiperazin-1-yI)-
acetamide
558.5
246
H3C
N-[4-({2-[(2-ftuoro-5-isopropyI-
phenyi)amino]-1-methyl-1 H-
benzimida2ol-5-yl}oxy)pyridin-2-yl]-
2-(4-methylpiperazin-1 -yl)-
acetamide
532.6
-129-
wo 2005/037273
PCT/US2004/034179
55trijf*tiirp
Name
MH+
247
F F
2-(4-methylpiperazin-1-yI)-N-{4-[(1-
methyl-2-{[4-(trifluoromethyI)-
phenyI]amino}-1H-benzimidazol-5-
y!)oxy]pyridin-2-yi}-acetannicie
540.6
248
F F
2-(4-methyipiperazin-1 -yi)-N-{4-[(1 -
methyl-2-{[4-(trifluoromethoxy)-
phenyl]amino}-1H-benzimidazoI"5-
yi)oxy]pyridin-2-yl}acetamide
556.6
249
F F
HjC CH3
2-(4-ethylpipera2in-1 -yI)~N-{4-[(1 -
methyl-2-{[4-(trifluoromethyl)-
phenyl]amino}-1H-benzimidazoi-5-
yl}oxy]pyridin-2-y!}acetamide
554.6
250
F F
0
2-(4-ethylpiperazin-1-yl)-N-{4-[(1-
methyl-2-{[4-(trifluoromethoxy)-
phenyl]amino}-1H-benzimidazol-5-
yl)oxy]pyridin-2-yl}acetamide
570.6
251
F^
2-(4-ethylpiperazin-1-yI)"N44-[(1^
methyl-2-{[3-(trifluoromethyl)-
phenyl]amino}-1H-benzimidazol-5-
yl)oxy]pyridin-2-yl}acetamide
554.6
252
F F
H3C
N-{4-[(2-{[2-fluoro-5-(trifluoro-
methyl)phenyl]amino}-1 -methyI-1 H-
ben2imidazol-5-yl)oxy]pyridin-2-yl}-
2-(1 H-imidazol-1-yl)acetamide
526.5
253
F F
N-{4-[(2-{[2-fluoro-5-(trifluoro-
methyi)phenyl]amino}-1 -methyi-1 H-
ben2imidazoi-5-yl)oxy]pyridin-2-yl}-
2-piperidin-1 -ylacetamide
543.5
264
F F
N-{4-[(2-{[2-fIuoro-5-(trifluoro-
methyl)phenyI]annino}-1 -methyl-l H-
benzimidazol-5-yl)oxy]pyridin-2-y!}-
2-(4-methyl-1 ,4-diazepan-1 -
yl)acetamide
572.6
-130-
wo 2005/037273
PCT/US2004/034179
Ex
55trii future
Name
MH+
255
N-{4-[(2-{[2-fluoro-5-(trifluoro-
methyl)phenyl]amino}-1-methyl-1H-
benzimidazoi-5-yi)oxy]pyridin-2-yl}-
2-(1 H-1 ,2,4-triaEol-1-yl)acetamic!e
527.5
256
F F
H3C
N-{4-[(2-{[2-chloro-5"(trif!uoro-
methyl)phenyl]amino}-1-methyl-1H-
benzimidazoI-5-yl)oxy]pyridin-2-yI}-
2-(1H-1,2,4-triazol-1-yl)acetamide
543.9
257
F F
N-{4-[(2-{[2-chloro-5-(trifiuoro-
methyi)phenyl]amino}-1-methyl-1H-
benzimidazol-5-yl)oxy]pyridin-2-yl}-
2-(4-methylpiperazin-1 -yl)-
acetamide
575
258
H3C CH3
N-{4-[(2-{[2-chloro-5-(trifiuoro-
methyl)phenyI]amino}-1-methyI-1H-
benzimidazol-5-yl)oxy]pyridin-2-yI}-
2-(4-methyl-1 ,4-diazepan-1-yl)-
acetamide
589
259
F F
H3C
2-(4-ethyl-1,4-diazepan-1-yl)-N-{4-
[(2-{[2-fluoro-6-(trifiuoro-
methyl)phenyl]amino}-1-methyl-1H-
benzimidazoI-5-yl)oxy]pyridin-2-yi}-
acetamide
586.6
260
F F
H3C
N-{4-[(2-{[2-chloro-5-(trifluoro-
methyl)phenyI]amino}-1-methyl-1H-
benzimidazol-5-yl)oxy]pyndin-2-yl}-
2-pyrrolidin-1 -ylacelamide
546
261
( V-F
ci
N-{4-[(24[4-chloro-3"(2-fluoro-
pyridin-4-yl)phenyl]amino}-1 -
methyM H-ben2imidazol-5-yl)-
oxy]pyridrn-2-yl}acetamide
503.9
262
N-[4-({2-[(3-tert-butylphenyl)amino]-
1,3-benzothiazol-5-y!}oxy)pyridin-2-
yl]acetamide
433-5
-131-
wo 2005/037273
PCT/US2004/034179
Qtriir^tiir^
263
o
2-(4-ethylpiperazin-1-yl)-N-[4-({2-
[(2-fluoro-5-pyriciin-3-yl-
phenyl)amino]-1-methyl-1 H-
ben2imiclazoi-5-yl}oxy)pyrid[n-2-
yl]acetamide
581.7
264
H3C
N-[4-({2-[(2-fluoro-5-isopropyl-
phenyI)amino]-1 -methyl-1 H-
benzimicIazol-5-yl}oxy)pyridin-2-
yl]acetamide
434.5
265
H3C
N-{4-[(2-{[2-fiuoro-3-(trifluoro-
methyl)phenyI]amino}-1-methyI-1H-
benzimida2ol-5-yl)oxy]pyridin-2-yl}-
1 -isopropylpiperidine-4-
carboxamide
571.6
266
N-{4-[(2-{[2-fluoro-4-(trifluoro-
methyl)phenyl]amino}-1 -methyl-1 H-
ben2imidazoI-6-yl)oxy]pyridin-2-yl}-
1 -isopropylpiperidine-4-
carboxamide
571.6
267
H3C
piperidin-4-yl 4-({2-[(4-fluoro-3-
tetrahydrofuran-3-yIphenyl)amino]-
1 -methyl-1 H-benzimidazol-S-
yl}oxy)pyridin-2-ylcarbamate
547.6
268
H3C
N-[4-({2-[(4-fluoro-3-isopropyl-
phenyl)anriino]-1 -methyl-1 H-
benzimida2ol-5-yl}oxy)pyridin-2-yl]-
2-morpholin-4-ylacetamide
519.6
269
H3C CH3 Chira)
H3C
(2S)-N-[4-({2-[(3-tert-butyl-
phenyl)amlno]-1 -methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-
yI]piperidlne-2-carboxamide
499.6
270
H3C Chira)
H3C
(2S)-N-[4-({2"[(2-fluoro-5-isopropyl-
phenyl)amino]-1 -methyl-1 H-
benzimidazol-5-yI}oxy)py^idin-2-
yl] piperidine-2-carboxamide
503.6
-132-
wo 2005/037273
PCT/US2004/034179
Ex
Structure
Name
■ wll 1 *
271
3
N-[4-({2-[(2-fluoro-5-pyridin-4-
ylphenyi)amino]-1-methyl-1 H-
ben2imidazol-5-yI}oxy)pyric!in-2-yl]-
2-pyrrolidin-1-ylacetamide
538.6
272
H3C
N-[4-({2-[(2,4-difluoro-5-isopropyl-
phenyl)amino]-1-methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
2-pyrrondin-1 -ylacetamide
521.6
273
N-[4-({2-[(2"fluoro-5'-pyridin-3-
ylphenyl)amino]-1-methyl-1 H-
benzfmidazoI-5-yl}oxy)pyridin-2-
yijcyclopropanecarboxamide
495.5
274
2-(4-ethylpiperazin-1-yl)-N-[4-({2-
[(2-fluoro-5-pyridin-3-
ylphenyl)amino]-1-methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-
yl]acetamide
581.7
275
2-(4-ethylpipera2in-1-y[)-N-[4-({2-
[(2-fluoro-5-pyridin-4-ylpheny!)-
amino]-1 -methyl-1 H-benzimidazol-
5-yl}oxy)pyridin-2-yl]acetamide
581.7
276
j7— N Chltal
N-[4-({2-[(2-fIuoro-5-pyridin-4-
ylphenyl)annino]-1-nnethyl-1 H-
ben2imidazoi-5-y!}oxy)pyridin-2-yl]-
2-[(2S)-2-(hydroxymethyl)pyrro!idin-
1-yl]acetamide
568.6
277
N-[4-({2-[(2-fluoro-5-pyridin-4-
ylphenyi)amino]-1 -methyi-1 H-
benzinnidazol-5-yl}oxy)pyridin-2-
yI]cyclopropanecarboxamide
495.5
278
N-[4-({2-[(2-fluoro-5-pyridin-3-
ylphenyl)amino]-1 -methyI-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
2-(4-methoxypiperidin-1 -
yl)acetamide
582.6
-133-
wo 2005/037273
PCT/US2004/034179
Ex.
279
280
281
282
283
284
285
286
Structure
H <
CH,chlral
N O
HX CH
H
H3C
HgC^ CH3
H
H3C
Chlral
CH,
H^C
H3C
CH,
H
N,
H3C
1^
CH3
CH,
Name
2-[(2R,4R)-2,4-dimethylazetidin-1
yI]_N-[4-({2-[(2-fluoro-5-pyridin-3-
yIphenyl)amino]-1-methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-
yl]acetamide
N-[4-({2-[(2-fiuoro-5-pyridin-3-
ylphenyl)amino]-1-methyl-1 H-
ben2imidazol-6-yl}oxy)pyridin-2-
yljacetamide
N-[4-({2-[(3-tert-butyi-4-fluoro-
pheny!)amino]-1-methyi-1H-
benzimidazol'5-yi}oxy)pyridin-2-yl]-
2-pyrro ndin-1 -ylacetamide
N-[4-({Z-[(5-tert-butyl-2-f!uoro-
phenyI)amino]-1-methyI-1 H-
ben2inniciazol-5-yl}oxy)pyridin-2-yll-
2-pyrroI idin-1-ylacetamide
(2S)-N-[4-({2-[(4-fluoro-3-isopropyl-
phenyI)amino]-1-methyl-1 H-
benzimicla2ol-5-yl}oxy)pyridin-2-
yl]piperidine-2-carboxamide
N-[4-({2-[(4-fluoro-3-isopropyl-
phenyi)amino]-1 -methyi-1 H-
benzimiclazol-5-yl}oxy)pyndin-2-yl]-
2-piperidlin-1-ylacetamide
MH+
552.6
N-[4-({2-[(2-fiuoro-6-pyridin-4-
ylphenyl)amino]-1-methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
2-(4'-methoxypiperidin-1-yI)-
acetamide
469.5
2-(4-methoxypiperidin-1-yl)-N-{4-
[(1-methyl-2-{[3-(trifluoromethy!)-
phenyl]annino}-1H-benzinnidazol-5-
y|)oxy]pyridin-2-yl}acetamide
517.6
517.6
503.6
517.6
582.6
555.6
-134-
wo 2005/037273
PCT/US2004/034179
ex.
MH+
287
H,C OH,
2-(4-methoxypiperidin-1-yl)-N-{4-
[(1-methyI-2-{[4-(trifluoromethyl)-
phenyI]amino}-1H-ben2imidazoi-5-
yl)oxy]pyric!in-2-y!}acetamicle
555.6
288
o
H3C
N-[4-({2-[(2-fluoro-5-pyridin-4-yI-
phenyl)amino]-1-methyl-1 H-
ben2imida2ol-5-y)}oxy)pyridin-2-yl]-
2-(3-methoxya2etidin-1 -yi)-
acetamide
554.6
289
H3C CH3
2-(3-methoxya2etidin-1 -yl)-N-{4-[(1 -
methyl-2-{[3-(trifluoromethyI)-
phenyI]amino}-1H-ben2innidazol-5-
yI}oxy]pyridin-2-yl}acetamide
527.5
290
H3C CH3
N-[4-({2-[(5-tert"butyi-2-fluoro-
phenyl)amino]-1-methyl-1 H-
benzinnida2oi-5-yl}oxy)pyridin-2-yi]-
2-(3"methoxya2etidin-1 -yl)-
acetamide
533.6
291
2-(3-methoxya2etidin-1-yl)-N-{4-[(1-
methyl-2-{[4-(trif!uoromethyl)-
pheny!]amino}-1H-ben2imidazol-5-
yl)oxy]pyridin-2-yl}acetamide
527,5
292
H3C
2-m ethoxy-N-(4-{[1 -methyl-2-({4-
t(trifluoromethyl)thio]phenyi}amino)-
1H'-ben2imidazol-5-yl]oxy}pyridin-2-
yl)acetamide
504.5
293
H3C
N-[4-({2-[(4-ethylphenyl)annino]-1-
methyl-1 H-benzimidazol-S-yl}-
oxy) pyridin-2-yi]-2-methoxy-
acetamide
432.5
294
H3C
N-[4-({2-[(3-tert-butylphenyl)amino]-
1 -methyi-l H-benzimidazol-5-yl}-
oxy)pyridin-2-yi]-2-methoxy-
acetamide
460.5
-135-
wo 2005/037273
PCT/US2004/034179
ex.
OLiUCrlLI rt?
■
MH+
295
F-4-F
H3C
N-{4-[(2-{[2-fluoro-5-(trifluoro-
methyI)phenyI]amino}-1 -methyl-1 H-
ben2imicia201-5-yl)oxy]pyridin-2-yl}-
2-methoxyacetamicle
490.4
296
hp
N-[4-({2-[(4-fluoro-3-tetrahyclro-
furan-3-ylphenyl)amino]-1-methyl-
1H-benzimidazol-5-yl}oxy)pyrjdin-2-
yl]-2-methoxyacetamide
492.5
297
F
H3C
N-{4-[( 1 -methyl-2-{[4-(trifluoro-
methyl)phenyl]annino}-1 H-
benzinriiclazol-5-yl)oxy]pyridin-2-yl}-
tetrahydrofuran-3-carboxamide
498.5
298
F )— CH3
H3C'
N-[4-({2-[(4-fluoro-3-isopropyl"
phenyl)amino]-1-methyf-1 H-
benzimidazol-5-yl}oxy)pyndin-2-yl]-
tetrahydrofuran-3-carboxamide
490.5
299
CH3
H3C
N-[4-({2-[(4-ethylphenyI)amino]-1-
methyl-1H-benzimidazol-5-yl}oxy)-
pyridin-2-yl]tetrahydrofuran-3-
carboxamide
468.5
300
H3C
VCH3
H3C
N-[4-({2-[(3-tert-butylphenyl)amino]-
1-nnethyi-1 H-benzimidazol-5-yl}-
oxy)pyridin-'2-yl]tetrahydrofuran-3-
carboxamide
486.6
301
H3C
N-{4-[(2-{[2-fluoro-5-(trifIuoro-
methyi)phenyl]amino}-1 -methyi-1 H-
benzimidazol-5-yl)oxy]pyridin-2-yl}-
tet ra h y d rof u ra n -3 -ca rb oxa m i d e
516.5
302
H3C'
N-[4-({2-[(4-fluoro-3-tetrahydro-
furan-3-ylphenyl)amino]-1-methyl-
1H-benzimida2ol-5-yl}oxy)pyridin-2-
yi]tetrahydrofuran-3-carboxamide
518.6
-136-
wo 2005/037273
PCT/US2004/034179
Ex.
Structure
Name
MH+
303
F
F-^
N-{4-[(1-methyI-2-{[4-{trifluoro-
methyl)phenyl]amino}-1 H-
ben2imlda20l-5-yI)oxy]pyridln-2-yl}-
tetrah yd rof u ra n -2-car boxa m i d e
498.5
304
H3C
H3C
N-[4-({2-[(4-f lu oro-3-isopropy 1-
phenyI)amino]-1-methyl-1H-
benzimidazol-5-yl}oxy)pyrid(n-2-yI]-
tetrahydrofuran-2-carboxamide
490.5
305
CH3
N-[4-({2-[(4-ethylphenyI)amino]-1-
methyI-1H-ben:2imida2oI-5-yl}oxy)-
pyridin-2-yntetrahydrofuran-2-
carboxamide
458.5
306
H3C
N-[4-({2"[(3-teft-butylphenyl)amino]-
1 -methyl-1 H-benzimidazoI-S-yl}-
oxy)pyridin-2-yI]tetrahydrofuran-2-
carboxamide
486.5
307
F
H3C
N-{4-[(2-{[2-fluoro-5-(trifluoro-
methyl)phenyl]amino}-1 -methyI-1 H-
ben2inriidazol-5-yl)oxy]pyridin-2-yl}-
tetrahydrofuran~2-carboxamide
516.5
308
N-[4-({2-[(4-fluDro-3-tetrahydro-
furan-3-yiphenyl)amino]-1-methyl-
1H-benzimidazol-5-yl}oxy)pyridin'-2-
yl]tetrahydrofuran-2-carboxamide
518.6
309
F
H3C
N_{4_[(1-methyl-2-{[3-(trifiuoro-
methyI)phenyl]amino}-1 H-
benzimidazol-5-yl)oxy]pyridin-2-yl-
tetrahydrofuran-2-carboxamide
498.5
310
F
F^F
S
H3C
N-(4-{[1-methyl-2-({4-[(trifluoro-
methyl)thlo]phenyl}amino)-1H-
benzimida2ol-6-yl]oxy}pyridin-2-
yl)tetrahydrofuran-2-carboxamide
530.5
-137-
wo 2005/037273
PCT/US2004/034179
Ex
Structure
Name
MH+
311
Br
N_[4-({2-[(4-bromophenyl)amino]-1-
methyl-1H-benzimidazol-5-yl}oxy)-
pyridin-2-yl]tetrahydrofuran-2-
carboxamide
509.4
312
F
0
H3C
N-{4-[(1-methyl-2'{[4-(trifiuoro-
methoxy)phenyI]amino}-1 H-
benzimidazol-5-yl)oxy]pyridin-2-yi}-
tetrahydrofuran-2-carboxamide
514.5
313
F
0
N'-'2-',N'-2— dimethyl-N-1'— {MCI-
methyl-2-{t4-(trifiuoromethoxy)-
phenyi]amino}-1H-benzinnidazoI-5-
yi)oxy]pyridin-2-yi}giycinamide
501.5
314
H3C
H3C
lsi^1^-[4-.({2-[(4"fluoro-3-isopropyl-
phenyl)amino]-1 -methyl-1 H-
benzirnidazol-5-y!}oxy)pyridin-2-yl]-
N-2'-,N'-'2— dimethylglycinamide
477.6
315
F F ^
N -2 N -2 ^-d i m eth y 1-N 1 — {4- [( 1 -
methyl-2-{[3-(trifIuoromethyl)-
phenyl]amino}-1H-benzimidazoi-5-
yj)oxy]pyrid in"2-yl}glycinamide
485.5
316
F F
H3C
N^1^-{4-[(2-{[2-fluoro-5-(trifluoro-
methyl)phenyl]amino}-1 -methyl-1 H-
benzimidazol-5-yl)oxy]pyridin-2-yl}-
N^2~,N-'2 — dimethylglycinamide
603.5
317
N^1~-[4-({2-[(3-tert-butylphenyl)-
amino]-1"methyl-1H-benzimidazol-
5-yI}oxy)pyridin-2-yI]-N~2'-,N--2—
dimethylglycinamide
473.6
318
H3C
N^1^-.[4-({2-[(4-ethylphenyl)amino]-
1 -methyl-1 H-benzimidazol-5-
yl}oxy)pyridin-2-yl]-N-2-',N-'2—
dimethylglycinamide
445.5
-138-
wo 2005/037273
PCT/US2004/034179
OLI UI^LUI «7
Name
MH+
319
H3C
N-{4-[(1-methyl-2-{[4-(trifiuoro-
methyl)phenyI]amino}-1 H-
benzimidazol-5-yl)oxy]pyridin-2-yi}-
pyrro!idine-3-carboxamicIe
497.5
320
F
H3C
N-{4-[(2-{[2-fluoro-5-(trifluoro-
methyI)phenyl]amino}-1 -methyl-1 H-
ben2imidazoI-5-yl)oxy]pyridin-2-yl}-
pyrroIidine-S-carboxamicJe
515.5
321
H3C
N-[4-({2-[(4-fluoro-3-isopropyl-
phenyl)amino]-1 -methyl- 1 H-
ben2imidazol-5-yl}oxy)py^idin-2-yl]-
pyrrolidine-3-carboxamide
489.6
322
N-[4-({2-[(4-fluoro-3-
tetrahydrofuran-3-ylphenyl)amino]-
1 -methyl-l H-benziinnidazol-5-yl}-
oxy)pyridin-2-yl]pyrrolidine-3-
carboxamide
517.6
323
F
H3C
N-{4-[(1 -methyl-2-{[3-(trif I uoro-
methyl)phenyl]amino}-1 H-
benzimidazol-5-yi)oxy]pyridin-2-yl}-
pyrrolidine-3-carboxamicIe
497,5
324
H3C
N-{4-[(1 -methyl-2-{[4-(trif I uoro-
nnethyl)phenyI]amino}-1 H-
benzimidazol-5-yi)oxy]pyridin-2-yl}-
piperidine-3-carboxam ide
511.5
325
>-CH3
H3C
N-[4-({2-[{2-fiuoro-5-isopropyl-
phenyl)amino]-1 -methyl-l H-
ben2imidazol-5-yl}oxy)pyridin-2-yl]-
pyrrolidine-3-carboxanriide
489.6
326
F
F_A-F
H3C
N-{4-[(1-methyl-2-{[4-(trifluoro-
methyl)phenyl]amino}-1 H-
benzimidazol-5-yl)oxy]pyridin-2-yl}-
tetrahydro-2H-pyran-4-
carboxamide
512.5
-139-
wo 2005/037273
PCT/US2004/034179
Ex,
Structure
Name
MH-f-
327
N-[4-({2-[(4-f!uoro-3-isopropyl-
phenyi)amino]-1-methyl-1 H-
benzimidazol-5-yf}oxy)pyriclin-2-yl]-
tetrahydro-2H-pyran-4-
carboxamide
504.6
328
H3C.
"V-CH3
H3C
N-[4-({2-[(2-fIuoro-5-isopropyl-
phenyl)amino]-1 -methyl-l H-
benzimida2ol-5-yl}oxy)pyridin-2-yi]-
tetrahydro-2H-pyran-4-
carboxamide
504.6
329
F F
H3C
N-{4-[(2-{[2-fluoro-5-(trif!uoro-
methyI)phenyI]amino}-1-methyl-1H-
ben2imidazoI-5-yl)oxy]pyridin-2-yl}-
tetrahydro-2H-pyran-4-
carboxamide
530.5
330
H3C.
H3C
N-[4-({2-[(3-tert-butylphenyl)amino]-
1-methyl-1 H-ben2im^dazoI-5-yl}-
oxy)py rid in-2-y l]tet rah y d ro-2 H-
py ra n -4-ca rb oxa m i d e
500.6
331
0,0
H3C
N-{4-[{2-{[4-chloro-3-(3-furyl)-
phenyl]amino}-1-methyI-1 H-
ben2imidazol-5-yl)oxy]pyridin-2-y!}-
acetamide
474.9
332
H.C
N-i — [4-({2-[(4-fluoro-3-tetrahydro-
furan-3-yfphenyl)amino]-1-methyl-
1H-benzimida2oI-5-yl}oxy)pyridin-2-
yi]giycinamide
477.5
333
H3C CH3
N^1^-[4_({2-[(3-tert"butylphenyI)-
amino]-1 -methyl-1 H-benzimidazol-
5-yl}oxy)pyridin-2-yl]gIycinamide
445.5
334
H3C
[sj-.^ — [4-({2-[(4-bromophenyl)-
aminol-l-methyl-IH-benzimidazol-
5-yI}oxy)pyridin-2-yl]glycinamide
468.3
-140-
wo 2005/037273
PCT/US2004/034179
Ex
StructurB
Name
MH+
335
F
H3C
N-^l '--{4-[(1 -methyl-2-{[3-
(trifluoronnethyl)phenyI]amino}-1H-
benzimicla2ol-5"yl)oxy]pyridin-2-
yl}glycinamide
457.4
336
F
F>-F
0
^-{4-[(1 -methyl-2-{[4-(trifiuoro-
methoxy)phenyl]amino}-1 H--
ben2imidazol-5-yl)oxy]pyridin-2-yl}-
glycinamide
473.4
337
F
H3C
— {4-[(1 -methy[-2-{I4-(trifiuoro-
methyI)phenyl]amino}-1 H-
ben2imidazoi"5-yi)oxy]pyridin-2-yl}-
glycinamide
457.4
338
F
H3C
N-1'--{4-[(2-{[2-fluoro-5-(trifluoro-
methyl)phenyl]amino}-1 -methyl-1 H-
benzimidazoi-5-yl)oxy]pyridin-2-yf}-
glycinamide
475.4
339
[4-({2-[(4-ethylphenyI)amino]-
1 -methyl-1 H-benzimidazoI-5-yI}-
oxy)pyridin-2-yi]gIycinamide
417.5
340
H3C
H3C
N-1--[4-({2-[(4--fluoro-3-isopropyl-
phenyi)amino]-1 -methyl-1 H-
benzimidazol-5-yi}oxy)py^id^n-2-yl]-
gjycinamide
449,5
341
F
F-^
H3G
'--{4-[(1 -methyl-2-{[4-(trifluoro-
methyl)phenyl]amino}-1 H-
benzim[da2ol-5-yl)oxy]pyridin-2-yl}-
L-alaninamide
471,5
342
F
H3C
N-1 '--{4-[(1 -methyl-2-{[3-(trifluoro-
methyl)phenyl]amlno}-1 H-
benzimidazol-5-yl)oxy]pyridin-2-yI}-
L-alaninamide
471.5
-141-
wo 2005/037273
PCT/US2004/034179
Ex.
Structure
Name
MH+
343
p F Chiral
H3C'
N'-l— {4-[(2-{[2-fluoro-5-(trifluoro-
nnethyl)phenyl]amino}-1-methyI-1H-
ben2imiclazol-5-yl)oxy]pyridin-2-yi}-
L-alaninamide
489.4
344
Br
H N--^^ 0 CH3
H3C
N-1 -'-[4-({2-[(4-bromophenyI)-
amino]-1-methyl-1H-benzimida2:ol-
5-yl}oxy)pyridin-2-yl]-N'-2'-,N'-2--
dimethylglycinamide
496.4
345
H hJ-A^ K^t^ 0 CH3
H3C
[4-({2-[(4-fluo^o-3-tetrahyciro-
fu^an-3-yIphenyl)amino]-1-methyI-
1H-ben2imida2ol-5-y^}oxy)py^idin-2-
yl]-N-2-',N-'2'-'-dimethyl-
glycinamide
505.6
346
H3C
N'-2'-, N-'2'-dimethyl-N'-1 — {4-[( 1 -
methyl-2-"{[4-(trifluoromethyl)-
pheny!]amino}-1H-benzimidazol-6-
yl)oxy]pyridin-2-yl}glycinamide
485.5
347
H3C
N-[4-({2-[(3-tert-butylphenyI)amino]-
1 -methyI-1 H-benzfmidazol-5-
yl}oxy)pyridin-2-yl]-L-proiinamide
485.6
348
/-^Q Chirat
N-[4-({2"[(4-fIuoro-3-tetrahydro-
furan-3-ylphenyI)amino]-1-methyl-
1H-benzimidazoI-5-yI}oxy)pyridin-2-
yl]-L-proiinamide
517.6
349
H3C
f
N-[4-({2-[(4-fiuoro-3-isopropyl-
phenyl)amino]-1 -methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
1 -isopropylpyrrolidine-3-
carboxamide
531.6
350
2-(ben2yloxy)-N-[4-({2-[(3-tert-
butyIphenyl)amino]-1 -methyl-1 H-
ben2imidazol-5-yl}oxy)pyridin-2-
yl]acetamide
536.6
-142-
wo 2005/037273
PCT/US2004/034179
Ex.
Structure
Name
351
2-(benzyloxy)-N-[4-({2-[(4-fluoro-3-
tetrahyclrofuran-3-ylphenyI)amino]-
1 -methyi-1 H-ben2imidazol-5-
yl}oxy)pyridin-2-yI]acetamide
568.6
352
H3C
H3C
N-[4-({2-[(3-tert-butyIphenyl)amino]-
1-methyl-1 H-ben2imida2oI-5-yl}-
oxy)pyridin-2-yl]-2-
hydroxyacetamide
1
446.5
353
F p
H3G
2-hydroxy-N-{4-[( 1 -methyi-2-{[4-
(trifluoromethyl)phenyl]amino}-1H-
ben2imida2ol-5-yl)oxy]pyridin-2-yl}-
acetamide
458.4
354
H3C CH3
/ — CH
/=( ^ OH
H3C
N-[4-({2-[(3-tert-butylphenyl)amino]-
1-methyl-1H-ben2imida2ol-5-
y l}oxy ) py rr d i n -2-y l]-3-h yd roxy-2"
(hydroxymethyl)-2-methyl-
propanamide
504.6
355
OH
H3C
N-[4-({2-[(4-fluoro-3-
tetrahydrofuran-3-ylphenyl)amino]-
1 -methyl-1 H-ben2imida2oI-5-yl}-
oxy ) py rid r n-2-y l]-3-h yd roxy-2-
(hydroxymethyI)-2-methyl-
DroDanamide
536.6
356
>=v OH
H3C
3-hydroxy-2-(hydroxymethyl)-2-
methyl-N-{4-[(1 -methyl-2-{[4-
(trifluoromethyl)phenyl]amino}-1H-
ben2imida2ol-5-yl)oxy]pyridin-2-yI}-
propanamide
516.5
357
H3C
OH
H3C
N-[4-({2-[(4-fluoro-3-isopropyI-
phenyI)amrno]-1 -methyl-1 H-
benzimida2oI-5-yl}oxy)pyndin-2-yl]-
3-hydroxy-2-(hydroxymethyI)-2-
methylpropanamide
508.6
358
H3C
H3C
N-[4-({2-[(4-fluoro-3-isopropyI-
phenyl)amino]-1 -methyI-1 H-
ben2imida2ol-5-yl}oxy)pyridin-2-yl]-
cyclopropanecarboxamide
460.5
-143-
wo 2005/037273
PCT/US2004/034179
Ex.
Structure
Name
359
H3C
H3C
N-[4-({2-[(2-fiuoro-5-isopropyl-
phenyl)amino]-1 -methyl-1 H-
benzimida2ol-5-yI}oxy)pyridin-2-yl]-
cyclopropanecarboxamide
460.5
360
F p
H3C
N-{4-[(1-methyl-2-{t4-(trifluoro-
methyl)phenyl]amino}-1 H-
benzimida2oI-5-yl)oxy]pyridin-2-yl}-
cyclopropanecarboxamide
468.-4
361
H t^-^K^ 0
H3C
N-[4-{{2-[(3-tert-butylphenyl)amino]-
1 -methyI-1 H-benzimidazoI-5-
yl}oxy)pyridin-2-yl]cyclopropane-
carboxamide
456.S
362
^^F HgC^CHs
1-isopropyl-N-{4-[(1-methyi-2-{[4-
(trifluoromethyl)phenyl]amino}-1H-
benzimidazol-5-yl)oxy]pyridin-2-
yl}piperidine-3-carboxamide
553.6
363
H3C
1 -isopropyi-N-{4-[( 1 -methyI-2-{I4-
(trifluoromethyl)phenyl]amino}-1H-
benzimidazol-5-yl)oxy]pyridin-2-
yl}pyrrolidine-3-carboxamide
539.6
364
P F OHChlral
(3S)-N-{4-[(2-{[2-fluoro-5-
(trifluoromethyl)phenyl]amino}-1-
methyl-1 H-benz(midazol-5-
yl)oxy]pyridin-2-yI}-1-(2-hydroxy-
ethyl)pyrrolidine-3-carboxamide
559.5
365
H3C
tert-butyl 4-({2-[(3-tert-butyIphenyI)-
aminol-l-methyl-IH-benzimidazol-
5-yi}oxy)pyridin-2-ylcarbamate
488.6
366
F 'VCH3
H N-A^ 0
H3C
methyl 4-({2-[(4-fluoro-3-isopropyl-
phenyl)amino]-1 -methyl-l H-
benzimidazol-5-yI}oxy)pyridin-2-yI-
carbamate
450.5
-144-
wo 2005/037273
PCT/US2004/034179
Ex.
Structure
Name
MH+
367
H3C
methyl 4-'({2-[(3-tert-butylphenyl)-
amino]-1 -methyl-l H-benzimidazol-
5-yI}oxy)pyridin-2-ylcarbamate
446.5
368
H3C
methyl 4-({2-[(4-fluoro-3-tetrahydro-
furan-3-ylphenyl)amino]-1-methyl-
1 H-benzimidazol-5-yl}oxy)pyridin-2-
ylcarbamate
478.6
369
Br
^} H methyl 4-({2-[(4-bromophenyl)-
^N_/Y^'^T^^Y°^''^^ amino]-1-methyl-1H-benzimidazol-
r* o-yij'Oxyjpynain-^-yicarDamate
469.3
370
F F 1
methyl 4-{[1-methyl-2-{{3-[(tnfluoro-
V/ MONO methyl)thio]phenyl}amino)-1H-
IPT' Y -cHa ben2imicla2ol-5-yl]oxy}pyridin-2-yl-
H N-^^ k^N 0 carbamate
490.5
371
^ ^ methyl 4-({2-[(4-ethyIphenyl}-
^N_//'^YY''TV ^""^^^3 amino]-1-methyl-1 H-benzimidazoi-
V'*" ° 5-yI}oxy)pyridin-2-yIcarbamate
418.5
372
^ F
f\1 methyl 4-[(1-methyl-2-{[4-(trifluoro-
\} H methyl)phenyl]amino}-1H-
^rg_/-[fY ^''''^ benzimidazol-5-yl)oxy]pyridin-2-yl-
r'' ° carbamate
458.4
373
H3C
/K """^ H ethyl 4-{{2-I(3-tert-butylphenyI)-
-/Y^^Y^^T^^^"' aminoJ-l-methyl-IH-benzimidazoi-
h"^n''^ 0 5-yl}oxy)pyridin-2-ylcarbamate
H3C
460.5
374
H3C
ethyl 4-({2-[(4-fluoro-3-tetrahydro-
furan-3-ylphenyI)amino]-1-methyl-
1H-benzimidazol-5-yl}oxy)pyridin-2-
ylcarbamate
492.5
-145-
wo 2005/037273
PCT/US2004/034179
5^11*1 ip'tiirA
wLI UVrLUI w
Nams
MH+
375
F y^^^3
H3C
ethyl 4-{{2-[(4-fluoro-3-isopropyl-
phenyi)amino]-1 -methyl-1 H-
benzimiclazol-5-yl}oxy)pyridin-2-yi-
carbamate
464.5
376
Br
H3C
ethyl 4-({2-[(4-bromophenyl)amino]-
1 -methyI-1 H-benzimidazol-S-yl}-
oxy ) py rid i n-2-y icarbam ate
483.3
377
CH3
H3C
ethyl 4-({2-[(4-ethylphenyl)amino]-
1-methyl-1 H-benzimidazol-5-yI}-
oxy)pyridin-2-ylcarbamate
432.5
378
'_7-CH3
H3C
plperidin-4-yl 4-({2-[(3-tert-butyl-
phenyl)amino]-1 -methyI-1 H-
benzimida2oI-5-yi}oxy)pyridin-2-yl-
carbamate
515.6
379
piperidin-4-yl 4-({2-[(4-fluoro-3-
tetrahydrofuran-3-ylphenyl)amino]-
1-methyt-1 H-benzimidazol-S-yl}-
oxy)pyridin-2-ylcarbamate
547.6
380
H3C
piperidin-4-yl 4-[(1 --methyI-2-{[4-
(trifIuoromethyI)phenyl]amino}-1H-
benzimidazol-5-yl)oxy]pyridin-2-
yicarbamate
527.5
381
Fn-CH3
H^C
piperidin-4-yl 4-({2-[(4-fluoro-3-
isopropylphenyl)amino]-1-methyl-
1H-benzimidazol-5-yl}oxy)pyridin-2-
ylcarbamate
519.6
382
H3C
piperidin-4-yI 4-[(1 -methyl-2-{[3-
(trifluoromethyl)phenyi]amino}-1H-
benzimidazol-5-yl)oxy]pyridin-2-
ylcarbamate
527.5
-146-
wo 2005/037273
PCT/US2004/034179
riiptiii'i^
Name
MH+
383
H3C
pipericiin-4-yl 4-"[{2-{[2-fluoro-5-
(trif!uoromethyl)phenyI]amino}-1-
methyl-1 H-benzimidazol-S-y!)-
oxy]pyridin-2"ylcarbamate
545.5
384
•^3^ CH3
1 -isopropyla2etidin-3-yl 4-({2~[(4-
fIuorO'-3-isopropy!pheny!)amino]-1-
methyl-l H-benzimidazol-5-yI}-
oxy)pyridin-2-ylcarbamate
533.6
385
CI. S< ,
H C
N-{4-[{2-{[4-chloro-3-(3-methyl-
tetrahydrofuran-3-yi)phenyl]amino}-
1 -methyI-1 H-benzimidazoi-S-yl)-
oxy]pyridin-2-yl}acetamide
493
386
H3C
H3CJVCH3
H3C
N-[4-({2-[(3-isopropyl-4-methyl-
phenyI)amino]-1-methyl-1H-
benzimidazol-5-yl}oxy)pyridin-2-yI]-
acetamide
- ■■ ■ — ' —
430.5
387
H 6
N-[4-({2-[(3-cyclopentyM-fIuoro-
phenyl)annino]-1 -methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
acetamide
460.5
388
H C
N-{4-[(1-methyl-2-{[3-(pentafluoro-
ethyl)phenyi]amino}-1 H-
benzimidazoI-5-yl)oxy]pyridin-2-y(}"
acetamide
492.4
389
X> X
N-{4-[(2'-{[4-fluoro-3-(3-methyl-
tetrahydrofuran-3-yl)phenyl]amino}-
1 -methyi-l H-benzimidazol-5-yl)-
oxy]pyridin-2-yl}acetannide
476.5
390
^ ^ H
nX7 X5^ X
H3C
M-{4-[(1-nnethy!-2-{[4-(pentafluoro-
ethyI)phenyl]amino}-1 H-
benzimidazol-6-yi)oxy]pyridin-2-yI}-
acetamide
492.4
-147-
wo 2005/037273
PCT/US2004/034179
Ex.
Structure
Name
MH+
391
H3C
N-[4-({2-[(4-fluoro-3-isopropyl-
pheny!)amino]-1 -methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-y!]-
1-nnethylpiperidine-4-carboxamide
517.6
392
1-methyl-N-{4-[(1 -methyl-2-{I4-
(pentafluoroethy!)phenyl]amino}-
1H-benzimidazoI-5-yI)oxy]pyridin-2-
yl}piperidine-4-carboxamide
575.6
393
H3CCH3
N-[4-({2-[(3-tert-butyi-4-chIoro-
phenyi)amino]-1 -methyI-1 H-
benzimidazoi-5-yi}oxy)pyridin"2-yI]-
1-ethylpiperidine-4-carboxamide
562.1
394
F
H3C
N-[4-({2-[(4-fluoro-3-isopropyi-
phenyl)amino]-1 -methyl-1 H-
ben2imidazol-5-yl}oxy)pyridin-2'-yl]-
piperidine-4-carboxamide
503.6
395
H3C
N-{4-[(1-methyl-2-{[4-(pentafIuoro-
ethyl)phenyl]annino}-1 H-
benzimidazol-5-yi)oxy]pyridin-2-yi}-
piperidine-4-carboxamide
561.5
396
F ^
H^C
N-{4-[(2-{[4-fluoro-3-(trifIuoro-
methyi)phenyl]amino}-1 -methyi-1 H-
benzimidazoI-5-yi)oxy]pyridin-2-yl}-
piperidine-4-carboxamide
529.5
397
F ^
H3C
N-{4-[(2-{[4-fiuoro-3"(trifluoro-
methyI)phenyl]amino}-1-methyI-1H-
benzimidazol-5-yi)oxy]pyridin-2-yl}-
acetamide
460.4
398
J — 'N F
N-[4-({2-[(4-fluoro-3-isopropyl-
phenyI)amino]-1 -methyl-1 H-
benzimidazol-5-yl}oxy)py^idin-2-yl]-
1-(2,2,2-trif!uoroethyi)piperidine-4-
carboxamide
585.6
-148-
wo 2005/037273 PCT/US2004/034179
Ex
Structure
Name
■
MH+
399
F
N-[4-({2-[(4-fluoro-3-isopropyl"
phenyl)amino]-1 -methyl-1 H-
ben2imiciazol-5-yl}oxy)pyridin-2-yl]-
N-methylacetamide
448.5
400
a-<;XJ Xj, I
N-[4-({2-[(2-f!uoro-5-isopropyl-
phenyi)amino]-1 -methyl-1 H-
ben2imidazol-5-yl}oxy)pyridin-2-yl]-
piperidine-4-carboxamide
503.6
401
1 -ethyl-N-[4-{{2-[{2-fiuoro-5-
isopropyIphenyl)amino]-1-methyl-
1H-benzimida2ol-5-yl}oxy)pyridin-2-
yl]piperidine-4-carboxamide
531.6
402
H3C
N-[4-{{2-[(2-fluoro-5-isopropyi-
phenyl)amino]-1 -methyl-1 H-
ben2imidazoI-5-yl}oxy)pyridin-2-yi]-
2-(4-isopropylpiperazin-1 -yl)-
acetamide
560.7
403
H3C
2-(4-ethylpiperazin-1-yi)-N-[4-({2-
[(2-fiuoro-5-isopropylphenyl)-
amino]-1 -methyl-1 H-benzimidazol-
5-yi}oxy)pyridin-2-yl]acetamide
546.7
404
H3C /=\
H3C
N-[4-({2-[(2-fluoro-5-isopropyl-
phenyl)amino]-1-methyM H-
benzi m id azol-5-y i}oxy ) py rid i n-2-y 1]-
acetamide
434.5
405
N-[4-({2-[(2-fIuoro-5-isopropyl-
phenyl)amino]-1 -methyl-1 H-
ben2imidazo[-5"yl}oxy)pyridin-2-yl]-
4-morpholin-4-ylbutanamide
547.6
406
N-[4-({2-[(2-fiuoro-5-isopropyI-
phenyl)amino]-1-methyl-1H-
ben2imidazol-5-yl}oxy)pyridin'-2-yl]-
1-methylpiperldine-4-carboxamide
517.6
-149-
wo 2005/037273
PCT/US2004/034179
Ex
Structure
Name
MH+
407
HjC^ /=\ Chiral
2-[(2R,6S)-2,6-dimethylmorpholin-
4-yI]-N-[4-({2-[(2-fluoro-5-isopropyl-
phenyl)amino]-1 -methyl-1 H-
benzimidazol-5-yl}oxy)pyndin-2-yl]-
acetamide
547.6
408
H,C
N-{4-[(2-{[4-fluoro-3-(3-methyl-
tetrahydrofuran-3-yI)phenyI]amino}-
1 -methyl-1 H-benzimidazol-S-
yi)oxy]pyridin-2-yI}-1-isopropyl-
piperidine-4-carboxamide
587.7
409
N-{4-[(2-{[2,4-difluoro-5-(trif!uoro-
nnethyl)phenyl]amino}-1 -methyl-1 H-
benzimidazol-5-yl)oxy]pyridin-2-yl}-
1 -isopropyIpipendine-4-
carboxamide
589.6
410
H3C
V-CH3 CH3
H3C
N-[4-({2-[(2-fluoro-5-isopropyl-
phenyl)amino]-1 -methyl-1 H-
benzimidazoi-5-yl}oxy)pyridin-2-yl]-
1-isopropylpiperidine-4-
carboxamide
545.7
411
H ll^N 0 CH3
H3C
N'-1'--{4-[(2-{[4-fluoro-3-(3-methyl-
tetrahydrofuran-3-yl)phenyl]amino}-
1 -methyl-1 H-benzimidazol-5-yl)-
oxy]pyridjn-2-yl}-N'-2-',N'-'2~-
dimethylglycinamide
519.6
412
F
H l^v^N 0 CH3
N-1 --{4-[(2-{[2,4-difluoro-5-
(trifluoromethyl)phenyi]amino}-1-
methyl-1 H-benzimidazol-5-yl)-
oxy]pyridin-2-yl}-N'-2'-,N'-2'^-
dimethylglycinamide
521.5
413
H3C
/>-CH3
H3C
N~1--[4-({2-[(2-fIuoro-5-isopropyl-
phenyl)amino]-1 -methyl-1 H-
benzimidazol-5-yi}oxy)pyridin-2"yl]-
N'-2'-,N'-2— dimethylglycinamide
477,6
414
F
N-{4-[(2-{[2,4-difiuoro-5-(trifluoro-
methyl)phenyl]amino}-1 -methyl-1 H-
benzimidazo]-5-yI)oxy]py^idin-2-yl}-
acetamide
478.4
-150-
wo 2005/037273
PCT/US2004/034179
OLrucLLirc?
IMCII 1 1«7
415
F
N-{4-[(2-{[2,4-difluoro-5-(trifluoro-
methyl)phenyl]anriino}-1 -methyi-1 H-
ben2imida20i-5-yi)oxy]pyridin-2-yl}-
1-ethylpiperidine-4-carboxamide
575.6
416
\ ( CH3
N-1'--{4-[(2-{[4-fluoro-3-(3-methyl-
tetrahydrofuran-3-yl)phenyl]am!no}-
1-methyl-1 H-benzimidazol-S-yl)-
oxy]pyridin-2-yI}glycinamide
491.5
417
f-KVf
N'-l '>'-{4-[(2-{[2,4-difluoro-5-
(trifluoromethyl)phenyl]amino}-1-
methyl-1H-benzimidazol-5-yl)oxy]-
pyridin-2-yi}glycinamide
493.4
418
H3C
H3C
N-1— [4-({2-[(2-f!uoro-5-isopropyl-
phenyl)amino]-1-methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
glycinamide
449.5
419
CH3
N-[4-({2-[(5-tert-butyl-2-fluoro-
phenyI)amino]-1-methyl-1H-
ben2imida2ol-5-yl}oxy)pyridin-2-yl]-
2-(4-isopropylpiperazin-1-yl)-
acetamide
574.7
420
H3C
N-[4-({2-[(5-tert-butyl-2-fluoro-
phenyl)amino]-1 -methyi-1 H-
benzimidazoI-5-yl}oxy)pyridin-2-yI]-
acetamide
448.5
1
421
H3C
N-[4-({2-[(3-tert-butyl-4-fluoro-
phenyl)amino]-1 -methyl-1 H-
ben2imida2ol-6-yl}oxy)pyridin-2-yl]-
acetamide
448.5
422
H^N-*^ ^ N 0 N CH3
H3C CH3
N-[4-({2-[(3-tert-butyl-4-fluoro-
phenyl)annino]-1 -methyi-1 H-
ben2imidazol-5-yl}oxy)pyridin-2-y!]-
2-(4-isopropylpiperazin-1-yl)-
acetamide
574.7
-151-
wo 2005/037273
PCT/US2004/034179
5^triif*tiir^
MH+
423
N-[4-({2-[(3-tert-butyI-4-fIuoro-
phenyl)amino]-1 -methy!-1 H-
ben2imidazol-5-yl}oxy)pyridin-2-yl]-
1 -isopropylpiperidine-4-
carboxamide
559.7
424
N-[4-({2-[(5-tert-butyl-2-fluoro-
phenyI)amino]-1-methyl-1H-
benzinnidazol-5-yl}oxy)pyridin-2-yl]-
1 -isopropyipiperidine-4-
carboxamide
559.7
425
N-{4-[(2-{[2-fluoro-4-(trifluoro-
nnethyI)phenyI]amino}-1 -methyl-1 H-
benzimidazol-5-yl)oxy]pyridin-2-yI}-
2-(4-isopropyipiperazin-1-yl)-
acetamide
586.6
426
F F
N-{4-[(2-{[2-fIuoro-5-(trifluoro-
methyl)phenyI]amino}-1 -methyl-1 H-
benzimidazol-5-yi)oxy]pyridin-2-yl}-
2-(4-methyl-1 ,4-diazepan-1 -yl)-
acetamide
572.6
427
H3C
N-{4-[(2-{[2-fluoro-5-(trifluoro-
methyl)phenyI]amino}-1 -methyl-l H-
benzimidazol-5-yl)oxy]pyridin-2-yl}-
2-[4-(2-hydroxyethyl)piperazin-1-
yl]acetamide
588.6
428
F F
Hc CH3
N-{4-[(2-{[2-fluoro-3-(trifluoro-
methyl)phenyl]amino}-1 -methyl-l H-
benzimidazoi-5-yl)oxy]pyridin-2-yl}-
2-(4-isopropylpiperazin-1 -yl)-
acetamide
586.6
429
N-{4-[(2-{[2-fluoro-3-(trifluoro-
methyI)pheny!]amino}-1-methyl-1H-
benzimidazoi-5-yl)oxy]pyridin-2-yl}-
1 -isopropylpiperidine-4-
carboxamide
571.6
430
N-{4-[(2-{[2-fluoro-4-(trifluoro-
methyl)phenyl]amino}-1 -methyl-1 H-
benzimidazol-5-yI}oxy]pyridin-2-y!}-
1 -isopropylpiperidrne-4-
carboxamide
571.6
-152-
wo 2005/037273
PCT/US2004/034179
MH+
1 mm. ■ H "
431
N-[4-({2-[(5-tert-butyi-2-fluoro-
phenyl)amino]-1-methyl-1 H-
benzimicla2oI-5-yI}oxy)pyridin-2-yI]-
1 -(2-hyciroxyethyI)piperidine-4-
carboxamide
561.7
432
H3C
N-{4-[(2-{[2-ch loro-4-(trif luoro-
methyl)phenyI]amino}-1-methyl-1H-
benzimidazol-5-yI)oxy]pyridin-2-yl}-
2-(4-ethylpipera2in-1-yl)acetamide
589
433
N-{4-[(2-{[2-chloro-4-(trifiuoro-
methyl)phenyl]amino}-1-methy!-1H-
benzimida2oI-5"yl)oxy]pyridin-2-yl}-
1 -isopropylpiperidine-4-
carboxamide
588
434
H3C-f-^f~V-CI H
H3C
N-[4-({2-[(5-tert-butyl-2-chloro-
phenyI)amino]-1 -nnethyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
2-(4-ethylpipera2in-1-yl)acetamide
577.1
435
H^C
N-[4-({2-[(5-tert-butyl-2-fluoro-
phenyl)amino]-1 -methyl-1 H-
benzinnidazol-5-yl}oxy)pyridin-2-yl]-
2-[4-(2-hydroxyethyl)piperazin-1-
yl]acetamide
576.7
436
N-[4-({2-[(5-tert-butyl-2-fiuoro-
phenyl)amino]-1 -methyl-1 H-
ben2imidazol-5-yl}oxy)pyridin-2"yi]-
2-[4-(2-methoxyethyl)piperazin-1-
yl]acetamide
590.7
437
0 ^^^^ "
N-(4-{[2-({3-[4-lnydroxy-1-(2,2,2-
trifIuoroethy!)piperidin-4-y!]-
phenyl}amino)-1-nnethyl-1 H-
ben2imidazol-5-yI]oxy}pyridin-2-yl)-
acetamide
555.5
438
r^F H
N-(4-{[2-({3-[4-methoxy-1-(2,2,2-
trifluoroethyl)piperidin-4-yl]-
phenyl}amino)-1 -methyl-1 H-
ben2imidazol-5-yl]oxy}pyridin-2-yI)-
acetamide
569.5
-153-
wo 2005/037273
PCT/US2004/034179
Structure
Name
MH+
439
C"^^ H PH3
[ J /==< 0
N-(4-{[1-methyJ-2-({3-[1-(2,2,2-
trifluoroethyl)piperidin-4-yI]-
phenyl}amino)-1H-ben2imida2ol-5-
yl]oxy}pyridin-2-yl)acetamicle
539.6
440
?^^3 H P^3
1 1 *^
^ CH3
N-{4-[(1-methyl-2-{[3-(1-methyl-
piperidin-4-yl)phenyl]amino}-1H-
benzimidazol-5-yI)oxy]pyridin-2-
yl}acetamide
471.6
441
N-[4-({2-[(3-tert-butylphenyl)amino]-
1-methyl-1H-benzimidazol-5-yl}-
oxy)pyridin-2-yl]-1-(2,2,2-trifluoro-
ethyl)piperidine-4-carboxamide
581.7
442
H3C
N-[4-({2-[(4-fluoro-3-tetrahydro-2H-
pyran-4-ylphenyl)amino]-1-methyl-
1H-benzimidazol-5-yl}oxy)pyridin-2-
yl]acetamide
476.3
443
F
0— |— F
H3C
N-{4-[(1-methyl-2-{[3-(trifluoro-
methoxy)phenyl]amino}-1 H-
benzimida2ol-5-yl)oxy]pyridin-2-yI}-
acetamide
458.3
444
P
H3C
N-[4-({1-methyl-2-[(3-tetrahydro-
2H-pyran-4-ylphenyl)amino]-1 H-
benzimidazo!-5-yI}oxy)pyridin-2-yl]-
acetamide
458.3
445
H N'-^v^ 0
(3R)- 1 -isopropyl-N-{4-[( 1 -methy i-2-
{[4-(trifluoromethyi)phenyl]amino}-
1H-benzimidazol-5-yl)oxy]pyridin-2-
yI}pyrrolidine-3-carboxamide
359.6
446
H3C
(3R)-N-[4-({2-[(4-fiuoro-3-isopropyl-
phenyl)amino]-1 -methyI-1 H-
benzimldazol-5-yl}oxy)pyridin-2-yl]-
1 -isopropyIpyrroiidine-3-
carboxamide
531.2
-154-
wo 2005/037273
PCT/US2004/034179
Structure
Name
MH+
447
(3R)-N-[4-({2-[(2-fluoro-5-isopropyl-
phenyl)amino]-1 -methyl-1 H-
ben2imidazol-6-yI}oxy)pyridin-2-yl]-
1-isopropylpyrrolidine-3-
carboxamide
531,2
448
H3C
(3R)-N-[4-({2-[(5-tert-butyl-2-fluoro-
phenyI)amino]-1 -methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
1 -isopropylpyrrolidine-3-
carboxamide
545.2
449
f\ u Chlral
^ H ig-A^ I^N 0
(3R)-N-{4-[(2-{[2-fluoro-5-(trif!uoro-
methyl)phenyl]am[no}-1 -methyl-1 H-
ben2imidazol-5-yl)oxy]pyridin-2-yl}-
1 -isopropylpyrrolidine-3-
carboxamide
557.1
450
H
N-[4-({2-[(3-tert-butylphenyl)-
amino]quinolin-6-yl}oxy)pyridin-2-
yi]acetamide
427.5
451
H3C
N-[4-({2-[(4-ch!oro-3-pyridin-4-
yiphenyI)amlno]-1 -methyl-1 H-
benzimidazoi-5-yl}oxy)pyridin-2-
yl]acetamide
485.9
452
H3C
\— N
H3C
N-{4-[(1 -methyl-2-{[4-(4-
methylpiperazin-1 -yj)phenyl]-
amino}-1 H-benzimidazol-5-yl)-
oxy]pyridin-2-yl}acetamide
472.6
453
H N-^^ 0
H3C
N-[4-({1-methyl-2-[(4-morpholin-4-
y!phenyl)amino]-1H-benzimidazol-
5-yl}oxy)pyridin-2-yI]acetamide
459.5
454
<r^N
=/ CI
H3C
N-{4-[(2-{[5-(2-chloropyridln-3-yl)-2-
fluorophenyl]amino}-1 -methyl-1 H-
benzimidazol-5-yl)-oxy]py^idin-2-
yl}acetamide
503.9
-155-
wo 2005/037273
PCT/US2004/034179
Ex.
Structure
Name
455
CI VK
N-{4-[(2-{[4-chioro-3-(2-chloro-
pyridin-3-yl)phenyl]annino}-1-
methyl-1 H-benzimidazoi-5-
yl)oxy]pyridin-2-yI}acetamicle
520.4
456
H3C
/K '''''
N-[4-({2-[(3-isopropylphenyl)-
amino]-1 ,3-ben2oxazol-5-yl}-
oxy)pyridin-2-yi]acetamide
403.5
457
N-[4-({2-[(3-tert-butylphenyl)-
amino]-1 -methyl-1 H-benzimidazol-
5-yl}oxy)pyridin-2-yl]-4-
methylpiperazine-1 -carboxamide
514.6
458
H3C CH3
CI y-cH3
H3C
N-[4-({2-[(3-tei1:-butyl-4-chloro-
phenyl)amino]-1 -methyl-1 H-
benzimidazoi-5-yl}oxy)pyridin-2-yil-
4-methylpipera2ine-1 -carboxamide
549.1
459
H3C
N-[4-({2-[(4-chloro-3-isopropyl-
phenyI)amino]-1 -methyl-1 H-
benzimidazol-5-yl}oxy)pyridin-2-yl]-
4-methylpiperazine-1 -carboxamide
535.1
460
N-[4-({2-[(4-fIuoro-3-isopropyI-
phenyl)amino]-1 -methyl-1 H-
benzimidazoI-5-yl}oxy)pyridin-2-yl]-
4-methyipiperazine-1 -carboxamide
518.6
461
F F
N-{4-[(2-{[2-fluoro-5-(trifluoro-
methyl)phenyl]amino}-1 -methyl-1 H-
benzimidazoi-5-yi)oxy]-pyridin-2-
yl}-4-methylpiperazine-1 -
carboxamide
544.5
462
H3G
N-[4-({2-[(3-tert-butylphenyl)-
amino]-1 -methyl-1 H-benzimidazol-
5-yl}oxy)pyridin-2-yl]pyrrolidine-3-
carboxamide
485.6
-156-
wo 2005/037273
PCT/US2004/034179
Ex.
Structure
Name
MH+
463
CH3
N-[4-({2-I(4-ethylphenyl)amino]-1-
methyl-1 H-benzimidazol-5-
yl}oxy)pyridin-2-yl]-1-isopropyI-
piperidine-4-carboxamicie
513.7
464
H3C
N-[4-({2-[(4-fluorophenyl)amino]-1-
methyl-l H-benzimidazoI-S-
yl}oxy)pyridin-2-yl]-1-isopropyl-
piperidine-4-carboxamide
503.6
465
H3C
F )— CH3
H3C CH3
N-[4-({2-[(2.4-difluoro-5-
isopropylphenyl)annino]-1-methyl-
1H"benzimidazol-5-yl}-oxy)pyridin-
2-yi]-2-(4-isopropyl-piperazin-1-
yl)acetannide
578.7
466
H3C
N-[4-({2-[(3-tert-butylisoxazol-5-
yl)amino]-1-methyl-1 H-
benzimldazo!-5-yl}oxy)pyridin-2-
yl]acetamide
421.5
467
F F
H3C
N-{4-[(2-{[2-fluoro-5-(trifluoro-
methyl)phenyl]amino}-1-methyl-1H-
benzimidazoI''5-yl)oxy]-pyridin-2-
yI}-2-(1H-pyrrol-1-yI)-acetamide
525.5
468
F
H3C
N-{4-[(2-{[2-chloro-5-(trifluoro-
methyl)phenyl]amino}-1-methyi-1H-
benzimidazoi-5-yl)oxy]-pyridin-2-
yl}-1-(2-hydroxy-ethyi)piperidine-4-
carboxamide
590.0
469
F p Ctilral
y^F
H3C
N-{4-[(2-{[2-fiuoro-5-(trifluoro-
methyl)phenyl]amino}-1-methyl-1H-
benzimidazol-5-yl}oxy]-pyridin-2-
yi}-2-[(3R)-3-hydroxy-pyrroiidin-1-
yljacetamide
545.5
470
'V-F CH3
H3C
N-{4-[(2-{[2-chioro-5-(trifiuoro-
methyl)phenyl]amino}-1-methyl-1H-
benzimidazoI-5-yl)oxy]-pyridin-2-
yl}-1 -isopropyl-piperidine-4-
carboxamide
588.0
-157-
wo 2005/037273
PCT/US2004/034179
Structure
Name
MH+
471
H3C
2-[(3R)-3-(dimethylamino)-
pyrrofidin-1-yI]-N-.{4-[(2-{[2-fluoro-5-
{trifiuoromethyl)-phenyl]amino}-1-
methyl-1 H-benzimidazol-S-
yi)oxy]pyridin-2-yi}acetamide
572.6
472
F F
H3C Vf
3 F F
N-{4-[(2-{[2-fluoro-5-(trifiuoro-
methyl)phenyl]amino}-1 -methyl-1 H-
ben2imidazol-5-yl)oxy]-pyridin-2-
yl}-2-[4-(trifluoro-methyl)-1 H-
imida2ol-1-yI]-acetannide
694.5
473
H3C.
H3C CH3
N-[4-({2-[(5-tert-butyI-2-fluoro-
phenyI)amino]-1 -methyl-1 H-
benzinnidazol-5-yl}oxy)pyridin-2-yl]-
2-(4-methoxypiperidin-1 -yl)-
acetamide
561.7
474
H3C CH3
N-[4-({2-[(3-ethylphenyf)amino]-1-
methyI-1 H-benzimidazol-S-
yi}oxy)pyridin-2-yl]-2-(3-
methoxyazetidin-1 -yl)acetamide
487.6
475
CH3
H3C CH3
N-[4-({2-[(4-ethylphenyl)amino]-1 -
methyl-1 H-benzimldazof-5-
yi}oxy)pyridin-2-yl]-2-(3-
methoxyazetidin-1 -yl)acetamide
487.6
476
H3C—
N-[4-({2-[(4-tert-butylphenyl)-
amino]-1 -methyl-1 H-benzimidazol-
5-yl}oxy)py^id^n-2'-y!]-2-{3-
methoxyazetidin-1 -yl)-acetamide
615.6
477
F F
H3C
1-ethyl-4-[2-({4-[(2-{[2-fIuoro-5-
(trifluoromethyl)phenyl]amino}-1-
methyl-1 H-benzimidazol-5-yl)-
oxy]pyridin-2-yl}amino)-2-oxoethyl]-
1-hydroxypiperazin-1-ium
589.6
478
F F
H3C
N-{4-[(2-{[2-fluoro-5-(trifluoro-
methyl)phenyl]amino}-1-methyl-1H-
ben2imidazol-5-yl)oxy]-pyridin-2-
yl}-2-piperazin-1 -yl-acetamide
544, 5
-158-
wo 2005/037273
PCT/US2004/034179
Ex.
Structure
Name
MH+
479
H y
CH3
N-(4-{[2-(cyclohexylamino)-1 -
methyl-1 H-benzimidazoi-S-
yi]oxy}pyridin-2-yl)acetamide
380.5
480
N-[4-({1 -methyl-2-[(1-phenyl-
ethyi)amino]-1 H-benzrmidazol-S-
yl}oxy)pyridin-2-yl]acetamide
402.5
481
N-(4-{[2-(mesitylamino)-1-methyl-
1H-benzimidazol-5-yl]-oxy}pyndin-
2-yl)acetamide
416.5
482
H 1
CH3
N-[4-({2-[(2,3-dimethyiphenyl)-
amino]-1-methyl-1H-benzimidazol-
5-y l}oxy ) py ri d i n-2-y I]aceta m id e
402.5
483
H
N-[4-({2-[(2-furylmethyl)amino]-1-
methyl-1 H-benzimidazol-5-
yl}oxy)pyridin-2-yi]acetamide
378.4
484
CH3 o'^^3 H
H (
CH3
N-[4-{{2-[(3,4-dlmethoxyphenyl)-
amino]-1 -methyl-1 H-benzimidazol-
5-y!}oxy)pyridin-2-yl]acetamide
434.5
485
JL ^ '
N-(4-{[2-(1,r-biphenyl-2-yl-amino)"
1 -methyl-1 H-benzimidazol-5-
yl]oxy}pyridin-2-yl)acetamide
450.5
486
H 1 .
CH3
N-{4-[(2-{[2-(4-chIorophenyi)-
ethyl]amino}-1 -methyl-1 H-
benzimidazol-5-yi)oxy]pyridin-2-
yi}acetamide
436.9
-159-
wo 2005/037273
PCT/US2004/034179
Ex.
Structure
Name
MH+
487
H I
CH3
N-(4-{[2-(isobutylamino)-1-methyl-
1H-benzimidazol-5-yl]-oxy}pyriciin-
2-yl)acetamicie
364.4
488
H3C K N
CH3
N-(4-{[2-(isopropylannino)-1-nnethyl-
1H-benzimida20l-5-yi]-oxy}pyridin'-
2-yI)acetamide
340.4
489
CH3
N-[4-({2-[(2-ethyl-6-methyI-
phenyl)amino]-1 -methyI-1 H-
ben2imidazol-5-yl}oxy)pyridin-2-
yl]acetamide
416.5
490
N-[4-({ 1 -methy l-2-t(3 ,4,5-
trimethoxyphenyl)amino]-1 H-
ben2imidazol-5-y[}oxy)pyridin-2-
yl]acetamide
464.5
491
^^3^ CH3
N-[4-({2-[(3,5-dimethyIphenyl)-
amino]-1 -methyl-1 H-benzimidazoi-
5-yl}oxy)pyridin-2-yl]acetam'ide
402.5
492
H^C-^ CH3
N-[4-({1 -methyl-2-[(4-methyI-
benzyi)amino]-1H-ben2imidazoI-5-
y[}oxy)pyridin-2-yi]acetamide
402.5
493
H 1
CH3
N-[4-({2-[(2-methoxy-5-methyl-
phenyl)amino]-1 -methyl-1 H-
ben2imidazoi-5-yl}oxy)pyridin-2-
yl]acetamide
418.5
494
H t
CH3
lSI-[4-({1 -nnethyI-2-[(4-phenoxy-
pyridin-3-yI)amino]-1 H-
benzimida2ol-5-yl}oxy)pyridin-2-
yl]acetamide
467.5
-160-
wo 2005/037273
PCT/US2004/034179
Ex.
Structure
Name
MH+
495
0
CH3
N-[4-({1-methyl-2-[(5-morphoiin-4-
yIpyridin-3-yl)amino]-1 H-
ben2imidazol-5-yl}oxy)pyridin-2-
yl]acetamide
460.5
496
y H V
N-[4-({1-methyl-2-[(5-methyl-3-
phenyiisoxa2ol-4-yi)amino]-1 H-
benzinnida2ol-5-yl}oxy)pyridin-2-
yl]acetamide
455.5
497
N-[4-({2-[(3,5-dimethylisoxazol-4-
yl)amino]-1-methyl-1 H-
ben2imidazol-5-yI}oxy)pyridin-2-
yl]acetamide
393.4
498
H "i
CH3
N-{4-[(1-methyl-2"{[2-(4-methyl-
phenyl)ethyi]amino}-1 H-
benzimidazol-5-yl)oxy]pyridin-2-
yl}acetamide
416.5
499
H 1
CH3
N-[4-({1-methyl-2-[(2-morpholin-4-
ylethyI)amino]-1H-ben2imidazol-5-
y l}oxy ) py rid i n-2-y 1] aceta m ide
411.5
500
H V
CH3
N-[4-({1 -methyl-2-[(2-piperidin-1 -
ylethyl)amino]-1 H-benzimidazol-5-
yi}oxy)pyridin-2-yl]acetamide
409.5
501
N-[4-({2-[(cyclohexylmethyl)-
annino]-1-methyl-1H-benzimida2ol-
5-yl}oxy)pyridin-2-yl]acetamide
394.5
502
CH3
N-(4-{[2-(2,3-dihydro-1H-inden-5-
ylamino)-1-methyl-1 H-
ben2imidazol-5-yl]oxy}pyridin-2-
yl)acetamide
414.5
-161-
wo 2005/037273
PCT/US2004/034179
Ex.
Structure
Name
MH+
,
503
N-[4-({1 -methyl-2-[(tetrahydro-
furan-2-yImethyI)amino]-1 H-
ben2imida2ol-5-yI}oxy)pyridin-2-
yl]acetamide
382.4
504
' H f
N-[4-({2-[(2,5-dimethylphenyl)-
amino]-1 -methyl-1 H-benzimidazol-
5-yl}oxy)pyridin-2-yl]acetamide
402.5
505
^ H 1
CH3
N-[4-({1 -methyl-2-[(2,4,5-
trinnethylphenyI)amino]-1 H-
benzimidazol-5-yI}oxy)pyridin-2-
yi]acetamide
416.6
506
H
H 1
N-(4-{[2-(cycfopentylamino)''1 -
methyl-l H-ben2imidazol-5-
yl]oxy}pyridin-2-yI)acetamide
366.4
507
H V
N-[4-({2-[(4-cyclohexylphenyl)-
annino]-1 -methyI-1 H-benzimidazol-
5-yl}oxy)pyridin-2-yl]acetamide
456.6
508
H 1
CH3
N-[4-({1 -methyl-2-I(4-phenoxy-
phenyl)annino]-1H-benzimidazoI-5-
y!}oxy)pyndin-2-yi]acetamide
466.5
509
N-[4-({2-[(2-ethoxyphenyl)-amino]-
1 -methyl-1 H-benzimidazol-5-
yl}oxy)pyridin-2-yl]acetamide
418.5
510
H 1
CH3
N-[4-({1 -methy!-2-[(2-phenyI-
ethyl)amino]-1 H-benzimidazoi-5-
yl}oxy)pyridin-2-yl]acetamide
402.5
-162-
wo 2005/037273
PCT/US2004/034179
Ex.
Structure
— — — ■
Name
MH+
511
H V
N-(4-{[1-methyl-2-(pyridin-3-yl-
amino)-1 H-benzimida2ol-5-yl]-
oxy}pyriciin-2-yl)acetamicie
375.4
512
H3C CH3
N-[4-({2-[(2-isopropylplrienyl)-
amino]-1-methyl-1H-benzimidazo!-
5-yl}oxy)pyridin-2-yi]acetannide
416.5
513
0 CH3
methyl 2-[(5-{[2-
(acetylamino)pyridin-4-yl]oxy}-1-
methyl-1 H-benzimida2ol-2-
yl)amino]butanoate
398.4
514
H
CH3
N-(5-{[2-(acetylamino)pyridin-4-
yl]oxy}-1 -methyi-1 H-benzimidazol-
2-yl)benzamide
402.4
515
H t
CH3
methyl 4-[(5-{[2-(acetyiamlno)-
pyridin-4-yl]oxy}-1-methyl-1 H-
benzimida2oi-2-yl)amino]-benzoate
432.4
Example 516
Raf/Mek Filtration Assay
Buffers
Assay buffer: 50 mM Tris, pH 7.5, 15 mM MgCl2, 0.1 mM EDTA, 1 mM DTT
Wash buffer: 25 mM Hepes, pH 7.4, 50 inM sodium pyrophosphate, 500 mM
NaCl
Stop reagent: BOmMEDTA
Materials
Raf, active: Upstate Biotech #14-352
Mek, inactive: Upstate Biotech #14-205
33P-ATP: NEN Perkin Elmer #NEG 602 h
-163-
wo 2005/037273
PCT/US2004/034179
96 well assay plates:
Filter apparatus:
96 well filtration plates:
Scintillation fluid:
Falcon U-bottom polypropylene plates #35-1190
Millipore #MAVM 096 OR
Millipore Immobilon 1 #MAIP NOB
Wallac OptiPhase "SuperMix" #1200-439
5
Assay conditions
Raf approximately 120 pM
Mek approximately 60 nM
33p-ATP 100 nM
Reaction time 45-60 minutes at room temperature
10 Assay protocol
Raf and Mek were combined at 2X final concentrations in assay buffer (50 mM
Tris, pH 7.5, 15 mM MgCl2. 0.1 mM EDTA and 1 mM DTT) and dispensed 15 jlxI per
well in polypropylene assay plates (Falcon U-bottom polypropylene 96 well assay plates
#35-1190. Backgroimd levels are determined in wells containing Mek and DMSO
1 5 without Raf.
To the Raf/Mek containing wells was added 3 )al of 1 OX of a raf kinase inhibitor
test compoimd diluted in 100% DMSO. The raf kinase activity reaction was started by
the addition of 12 |Ltl per well of 2.5X ^^P-ATP diluted in assay buffer. After 45-60
minutes, the reactions were stopped with the addition of 70 jxl of stop reagent (30 mM
20 EDTA). Filtration plates were pre- wetted for 5 min with 70% ethanol, and then rinsed by
filtration with wash buffer. Samples (90 )li1) from the reaction wells were then transferred
to the filtration plates. The filtration plates were washed 6X with wash buffer using
Millipore filtration apparatus. The plates were dried and 100 |j-l per well of scintillation
fluid (Wallac OptiPhase "SuperMix" #1200-439) was added. The CPM is then
25 determined using a Wallac Microbeta 1450 reader.
30 Raf and mutant B-Raf (V599E); see, for example, "Mechanism of Activation of the RAF-
ERK Signaling Pathway by Oncogenic Mutations of B-RAF'\ Cell 116: 855-867 (March
19, 2004); and "Dynamic Changes in C-Raf Phosphorylation and 14-3-3 Protein Binding
Example 517
ASSAY 2: Biotinvlated Raf Screen
In Vitf'o Raf Screen
The activity of various isofomis of Raf serine/threonine kinases (e.g., c-Raf, B-
-164-
wo 2005/037273
PCT/US2004/034179
in Response to Growth Factor Stimulation - Differential Roles Of 14-3-3 Protein Binding
Sites", Journal of Biological Chemistry 279(14): 14074-14086 (April 2, 2004)) can be
measured by providing ATP, MEK substrate, and assaying the transfer of phosphate
moiety to the MEK residue. Recombinant isoforms of Raf were obtained by purification
5 from sf9 insect cells infected with a human Raf recombinant baculovims expression
vector. Recombinant kinase inactive MEK was expressed in E. coli and labeled with
Biotin post purification. For each assay, test compounds were serially diluted in DMSO
then mixed with Raf (0.50 nM) and kinase inactive biotin-MEK (50 nM) in reaction
buffer plus ATP (1 \xM), Reactions were subsequently incubated for 2 hours at room
10 temperature and stopped by the addition of 0.5 M EDTA. Stopped reaction mixture was
transferred to a neutradavin-coated plate (Pierce) and incubated for 1 hour.
Phosphorylated product was measured with the DELFIA time-resolved fluorescence
system (Wallac), using a rabbit anti-p-MEK (Cell Signaling) as the primary antibody and
europium labeled anti-rabbit as the secondary antibody. Time resolved fluorescence was
15 read on a Wallac 1232 DELFIA fluorometer. The concentration of each compound for
50% inhibition (IC5Q) was calculated by non-linear regression using XL Fit data analysis
software.
Using the procedures of Example 517, the compounds of Examples 1-466, 468-
476 and 478 were shown to have a raf kinase inhibitory activity at an IC5Q of less than 10
20 \xM.
While the preferred embodiments of the invention has been illustrated and
described, it will be ajppreciated that various changes can be made therein without
departing from the spirit and scope of the invention.
25
-165-
wo 2005/037273
PCT/US2004/034179
The embodiments of the invention in which an exclusive property or privilege is
claimed are defined as follows:
wherein, Xi and X3 are independently selected from -NR4-, -O- or — wherein
R4 is hydrogen or loweralkyl, provided that at least one of Xi and X3 must be N or -NR4-;
X2 is -NH- or -(CH2)m- ? wherein m is 0, 1, 2, 3 or 4;
A| is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl,
polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryU or
hetero ary Iheter o ary 1 ;
Rj is hydrogen or substituted or unsubstituted loweralkyl, alkoxyalkyl,
loweralkyloxy, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
alkyloxyalkylheterocycloalkyl, hetero arylalkyl, cycloalkyloweralkyl, heterocycloalkyl-
loweralkyl, loweralkylheterocycloalkyl, arylloweralkyl, heteroarylloweralkyl, alkyloxy-
alkylheterocycloloweralkyl, or heteroarylloweralkyl;
R2 is hydrogen or loweralkyl;
each R3 and R3' are independently selected from hydrogen, halogen, hydroxy,
cyano, loweralkyl, or loweralkoxy; and
p and q are independently 0, 1 , 2 or 3 ; or
a pharmaceutically acceptable salt, ester or prodrug thereof.
2. A compound of Claim 1 wherein Xi is -NR4-.
3 . A compound of Claim 2 wherein R4 is hydrogen.
4. A compound of Claim 2 wherein R4 is methyl.
5. A compound of Claim 1 wherein X2 is — NH-,
A compoxmd of the formula (I):
R2
(I)
-166-
wo 2005/037273
PCT/US2004/034179
6.
A compound of Claim 1 wherein is selected from the group consisting
of substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl,
pyrimidinylalkyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkyl-
phenyl, chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, dihalophenyl, nitro-
phenyl, 4-bromophenyl, 4-chlorophenyl, alkylbenzoate, alkoxyphenyl, dialkoxyphenyl,
dialkylphenyl, trialkylphenyl, thiophene, thiophene-2-carboxylate, alkylthiophenyl,
trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, biphenyl, cyclohexylphenyl,
phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl^ alkylchlorophenyl, alkyl-
fluorophenyl, trifluoromethylchlorophenyl, trifluoromethylbromophenyl indenyl^ 2,3-
dihydroindenyl, tetralinyl, trifluorophenyl, (trifluoromethyl)thiophenyl, alkoxybiphenyl,
morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl,
indolyl, 23-dihydroindolyl, l-aceytl-23-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-
2-yl5 hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin- 1 -yl, pyrrolidin-1-
ylalkyU 4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamaatyl, bicyclohexyl,
quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl, phenylimidazolyl,
pthalamido, napthyl, benzophenone, anilinyl, anisolyl, quinolinyl, quinolinonyl,
phenylsulfonyl, phenylalkylsulfonyl, 9H-fluoren-l-yl, piperidin- 1 -yl, piperiditi-1-ylalkyl,
cyclopropyl, cyclopropylalkyl, pyximidin-S-ylphenyl, quinolidinylphenyl, furanyl,
furanylphenyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl5 4-diazepan- 1 -yl,
hydroxypyrrolidn-l-yl, dialkylaminopyrrolidin-1 -yl, l,4'-bipiperidin-r-yl5 and (1,4'-
bipiperidin- 1 '-ylcarbonyl)phenyl.
7. A compound of Claim 1 wherein Ai has the structure:
wherein R5, R75 Rg and R9 are independently selected from hydrogen, halo,
loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy, haloloweralkyloxy,
loweralkylthio, haloloweralkylthio, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl.
R7
-167-
wo 2005/037273
PCT/US2004/034179
8. A compoimd of Claim 7 wherein R5, Rg^ R75 Rg and R9 are independently
selected from hydrogen, chloro, fluoro, methyl, ethyl, propyl, z^o-propyl, butyl, /e/Y-butyl,
cyano, hydroxy, methyloxy, trifluoromethyl, triftuoromethoxy, trifluoromethylthio,
acetyl, and substituted or unsubstituted phenyl, phenyloxy, furyl, tetrahydrofuranyl,
tetrahydropyranyl, pyridinyl, trifluoromethylpiperidinyl, thiophenyl, piperazinyl, and
morpholinyl.
9. A compoamd of Claim 1 wherein Rj has the structure:
R12
wherein n is 0, 1 , 2, 3 or 4;
r is 1 or 2;
X4 is -CH- or N
RjQ and R22 independently selected from hydrogen, halo, loweralkyl,
haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkyl-
sulfonyl, haloloweralkylsulfonyl, and substituted or xmsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl; and
Rjl is hydrogen, loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy,
haloloweralkyloxy, loweralkyloxyloweralkyl, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl.
10. A compound of Claim 9 wherein n is 1 .
11. A compoxmd of Claim 9 wherein R^q R12 are hydrogen or loweralkyl.
12. A compovind of Claim 9 wherein R^ 1 is loweralkyl.
13. A compoimd of the formula (II) :
-168-
wo 2005/037273
PCT/US2004/034179
wherein, X2 is -NH- or "(CH2)m- . wherein m is 0, 1 , 2, 3 or 4;
Aj is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl,
polycycHc aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, or
heteroarylheteroaryl;
Rl is hydrogen or substituted or imsubstituted loweralkyl, alkoxyalkyl,
loweralkyloxy, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
alkyloxyalkylheterocycloalkyl, heteroarylalkyl, cycloalkyloweralkyl, heterocycloalkyl-
loweralkyl, loweralkylheterocycloalkyl, arylloweralkyU heteroarylloweralkyl, alkyloxy-
alkylheterocycloloweralkyl, or heteroarylloweralkyl;
R2 is hydrogen or loweralkyl;
R3 is hydrogen, halogen, loweralkyl, or loweralkoxy; and
R4 is hydrogen or loweralkyl or
a pharmaceutically acceptable salt, ester or prodrug thereof.
14. A compound of Claim 13 wherein R4 is hydrogen.
15. A compound of Claim 13 wherein R4 is methyl.
16. A compouad of Claim 13 wherein X2 is -NH-.
17. A compound of Claim 13 wherein A^ is selected from the group consisting
of substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl,
pyrimidinylalkyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkyl-
phenyl, chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, dihalophenyl, nitro-
phenyl, 4-bromophenyl, 4-chlorophenyl, alkylbenzoate, alkoxyphenyl, dialkoxyphenyl,
dialkylphenyl, trialkylphenyl, thiophene, thiophene-2-carboxylate, alkylthiophenyl,
trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, biphenyl, cyclohexylphenyl,
phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl, alkylchlorophenyl, alkyl-
fluorophenyl, trifluoromethylchlorophenyl, trifluoromethylbromophenyl indenyl, 2,3-
dihydroindenyl, tetralinyl, trifluorophenyl, (trifluoromethyl)thiophenyl, alkoxybiphenyl.
-169-
wo 2005/037273
PCT/US2004/034179
morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl,
indolyl, 23-dihydromdolyl, l-aceytl-23-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-
2-yl, hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin- 1 -yl, pyrrolidin- 1 -
ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl, bicyclohexyl,
quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl, phenylimidazolyl,
pthalamido, napthyl, benzophenone, anilinyl^ anisolyl, quinolinyl, quinolinonyl,
phenylsulfonyl, phenylalkylsulfonyl, 9H-fluoren- 1 -yl, piperidin-l-yl, piperidin-1-ylalkyl,
cyclopropyl, cyclopropylalkyl, pyrimidin-S-ylphenyl, quinolidinylphenyl, furanyl,
furanylphenyl, N-methylpiperidin-4-yI, pyrrolidm-4-ylpyridinyl, 4-dia2epan- 1 -yl,
hy droxypyrrolida-1 -yl, dialkylaminopyrrolidin- 1 -yl, 1 ,4'-bipiperidin- 1 '-yl, and (1 A'-
bipiperidin- 1 '-ylcarbonyl)phenyL
18, A compound of Claim 13 wherein A| has the structure:
wherein R5, R5, R7, Rg and R9 are independently selected from hydrogen, halo,
loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy, haloloweralkyloxy,
loweralkylthio, haloloweralkylthio, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl,
19. A compound of Claim 18 wherein R5, R5, R7, R3 and R9 are
independently selected from hydrogen, chloro, fluoro, methyl, ethyl, propyl, z^-o-propyl,
butyl, tert-butyU cyano, hydroxy, methyloxy, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, acetyl, and substituted or unsubstituted phenyl, phenyloxy, furyl,
tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, trifluoromethylpiperidinyl, thiophenyl,
piperazinyl, and morpholinyL
20. A compound of Claim 13 wherein R^ has the structure:
R7
R5
-170-
wo 2005/037273
PCT/US2004/034179
(CH2)n^
wherein n is 0, 1, 2, 3 or 4;
r is 1 or 2;
X4 is -CH- or N
R^O and R12 independently selected from hydrogen, halo, loweralkyl,
haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkyl-
sulfonyl, haloloweralkylsulfonyl, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl; and
Rll is hydrogen, loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy,
haloloweralkyloxy, loweralkyloxyloweralkyl, and substituted or unsubstituted cycloalkyl,
heterocycloalkylj aryl, or heteroaryl.
21. A compound of Claim 20 wherein nisi.
22. A compoixad of claim 20 wherein R^q and K12 are hydrogen or loweralkyl.
26. A compound of Claim 20 wherein Rji is loweralkyl.
27 . A compound of the formula (III) :
wherein, Xi is -NR4-, -O- or -S-, wherein R4 is hydrogen or loweralkyl;
X2 is — NH- or --(CH2)m- , wherein m is 0, 1, 2, 3 or 4;
Aj is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl,
polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, or
heteroarylheteroaryl;
Rj is hydrogen or substituted or unsubstituted loweralkyl, alkoxyalkyl,
loweralkyloxy, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
R2
(HI)
-171-
wo 2005/037273
PCT/US2004/034179
alkyloxyalkylheterocycloalkyl, heteroarylalkyl, cycloalkyloweralkyl, heterocycloalkyl-
loweralkyU loweralkylheterocycloalkyl, arylloweralkyl, heteroarylloweralkyl, alkyloxy-
alkylheterocycloloweralkyl, or heteroarylloweralkyl;
R2 is hydrogen or loweralkyl; and
R3 is hydrogen, halogen, loweralkyl, or loweralkoxy; or
a pharmaceutically acceptable salt, ester or prodrug thereof.
28. A compound of Claim 27 wherein Xi is -NR4-.
29. A compound of Claim 28 wherein R4 is hydrogen.
30. A compound of Claim 28 wherein R4 is methyl.
31. A compound of Claim 27 wherein X2 is -NH-.
32. A compound of Claim 27 wherein Aj is selected from the group consisting
of substituted or xmsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pjoridylalkyl,
pyrimidinylalkyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkyl-
phenylj chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, dihalophenyl, nitro-
phenyl, 4-bromophenyl, 4-chlorophenyl, alkylbenzoate, alkoxyphenyl, dialkoxyphenyl,
dialkylphenyl, trialkylphenyl, thiophene^ thiophene-2-carboxylate, alkylthiophenyl,
trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, biphenyl, cyclohexylphenyl,
phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl, alkylchlorophenyl, alkyl-
fluorophenyU trifluoromethylchlorophenyl, triflnoromethylbromophenyl indenyl, 2,3 -
dihydroindenyl, tetralinyl, trifluorophenyl, (trifLuoromethyl)thiophenyl, alkoxybiphenyl,
morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl,
indolyl, 2,3-dihydroindolyl, l-aceytl-2,3-dihydroindolyl, cycloheptyl, bicyclo [2.2.1 ]hept-
2-yl, hydroxyphenyl, hydroxyalkylphenyl, pyrrolidinyl, pyrrolidin-l-yl, pyrrolidin- 1 -
ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl, bicyclohexyl,
quinuclidinyl, imidazolyl^ benzimidazolyl, imidazolylphenyl, phenylimidazolyl,
pthalamido, napthyl, benzophenone, atiilinyl, anisolyl, quinolinyl, quinolinonyl,
phenylsulfonyl, phenylalkylsulfonyl, 9H-fluoren- 1 -yl, piperidin- 1 -yl, piperidin-1-ylalkyl,
cyclopropyl, cyclopropylalkyl, pyrimidin-5-ylphenyl, quinolidinylphenyl, furanyl,
furanylphenyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan- 1 -yl,
-172-
wo 2005/037273
PCT/US2004/034179
hydroxypyrrolidn- 1 -yl, dialkylaminopyrrolidin- 1 -yl, 1 ,4'-bipiperidin- 1 '-yl, and ( 1 ,4'-
bipiperidin- 1 -ylcarbonyl)phenyl.
33. A compound of Claim 30 wherein Ai has the structure:
wherein R5, R^, R7, and R9 are independently selected from hydrogen, halo,
loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy, haloloweralkyloxy,
loweralkylthio, haloloweralkylthio, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl.
34. A compound of Claim 33 wherein R5, R^, R7, Rg and R9 are
independently selected from hydrogen, chloro, fluoro, methyl, ethyl, propyl, z^o-propyl,
butyl, tert-hntyl, cyano, hydroxy, methyloxy, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, acetyl, and substituted or unsubstituted phenyl, phenyloxy, furyl,
tetrahydrofijranyl, tetrahydropyranyl, pyridinyl, trifluoromethylpiperidinyl, thiophenyl,
piperazinyl, and morpholinyl.
34. A compoxmd of Claim 27 wherein Rj has the structure:
wherein n is 0, 1, 2, 3 or 4;
r is 1 or 2;
X4 is -CH- or N
Rio and R12 are independently selected from hydrogen, halo, loweralkyl,
haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkyl-
sulfonyl, haloloweralkylsulfonyl, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl; and
-173-
wo 2005/037273
PCT/US2004/034179
R^i is hydrogen, loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy,
haloloweralkyloxy, loweralkyloxyloweralkyl, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl.
35. A compound of Claim 34 wherein n is 1 .
36. A compound of Claim 34 wherein R^q are hydrogen or
loweralkyl.
37. A compoiHid of Claim 34 wherein R^ i is loweralkyl.
38. A compoimd of the formula (IV):
wherein Xi is -NR4-5 -O- or -S-, wherein R4 is hydrogen or loweralkyl;
Ai is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl,
polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, or
heteroarylheteroaryl;
Kl is hydrogen or substituted or unsubstituted loweralkyl, alkoxyalkyl,
loweralkyloxy, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
alkyloxyalkylheterocycloalkyl, heteroarylalkyl, cycloalkyloweralkyl, heterocycloalkyl-
loweralkyl, loweralkylheterocycloalkyl, arylloweralkyl, heteroarylloweralkyl, alkyloxy-
alkylheterocycloloweralkyl, or heteroarylloweralkyl;
R2 is hydrogen or loweralkyl; and
R3 is hydrogen, halogen, loweralkyl, or loweralkoxy; or
a pharmaceutically acceptable salt, ester or prodrug thereof.
39. A compound of Claim 38 wherein Xi is -NR4-.
40. A compoimd of Claim 39 wherein R4 is hydrogen.
41 . A compoimd of Claim 39 wherein R4 is methyl.
R2
(IV)
-174-
wo 2005/037273
PCT/US2004/034179
42. A compound of Claim 38 wherein is selected from the group consisting
of substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, phenylalkyl, pyridylalkyl,
pyrimidinylalkyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkyl-
phenyl, chlorophenyl, fluorophenyl, bromophenyl, iodophenyl, dihalophenyl, nitro-
phenyl, 4-bromophenyl, 4-chlorophenyl, alkylbenzoate, alkoxyphenyl, dialkoxyphenyl,
dialkylphenyl, trialkylphenyl, thiophene, thiophene-2-carboxylate, alkylthiophenyl,
trifluoromethylphenyl, acetylphenyl, sulfamoylphenyl, biphenyl, cyclohexylphenyl,
phenyloxyphenyl, dialkylaminophenyl, alkylbromophenyl, alkylchlorophenyl, alkyl-
fluorophenyl, trifluoromethylchlorophenyl, trifluoromethylbromophenyl indenyl, 2,3-
dihydroindenyl, tetralinyl, trifluorophenyl, (trifluoromethyl)thiophenyl, alkoxybiphenyl,
morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyU cyclohexylalkyl,
indolyl, 23-dihydroindolyl, l-aceytl-23-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-
2-yl, hydroxyphenyl, hydroxyalkylphenyU pyrrolidinyl, pyrrolidin-l-yl, pyrrolidin-l-
ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl, bicyclohexyl,
quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl, phenylimidazolyU
pthalamido, napthyl, benzophenone, anilinyl, anisolyl, quinolinyl, quinolinonyl,
phenylsulfonyl, phenylalkylsulfonyl, 9H-fluoren- 1 -yl, piperidin-l-yl, piperidin- 1 -ylalkyl,
cy clopropyl, cyclopropylalkyl, pyrimidin-5 -ylphenyl, quinolidinylphenyl, furanyl,
furanylphenyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan- 1-yl,
hy droxypyrrolidn- 1 -yl, dialkylaminopyrrolidin- 1 -yl, 1 ,4'-bipiperidin- 1 -yl, and ( 1 ,4-
bipiperidin- 1 '-ylcarbonyl)phenyL
43 . A compound of Claim 3 8 wherein Ai has the structure:
wherein R5, R7, Rg and R9 are independently selected from hydrogen, halo,
loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy, haloloweralkyloxy,
loweralkylthio, haloloweralkyltWo, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl.
-175-
wo 2005/037273
PCT/US2004/034179
44. A compound of Claim 38 wherein R5, R5, R75 Rg and R9 are
independently selected from hydrogen, chloro, fluoro, methyl, ethyl, propyl, z^o-propyl,
butyl, ^er^butyl, cyano, hydroxy, methyloxy, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, acetyl, and substituted or unsubstituted phenyl, phenyloxy, furyl,
tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, trifluoromethylpiperidinyl, thiophenyl,
piperazhayl, and morpholinyl.
45. A compound of Claim 38 wherein Rj has the stmcture:
wherein n is 0, 1 , 2, 3 or 4;
r is 1 or 2;
X4 is -CH- or N
Rjo and R12 are independently selected from hydrogen, halo, loweralkyl,
haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkyl-
sulfonyl, haloloweralkylsulfonyl, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl; and
Rll is hydrogen, loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy,
haloloweralkyloxy, loweralkyloxyloweralkyl, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl.
46. A compound of Claim 45 wherein n is 1 .
47. A compound of Claim 45 wherein R^q and R12 are hydrogen or
loweralkyl.
48. A compound of Claim 45 wherein R^ i is loweralkyl.
49. A compound of the formula (V):
R12
-176-
wo 2005/037273
PCT/US2004/034179
wherein Ri is hydrogen or substituted or xmsubstituted loweralkyl, alkoxyalkyl,
loweralkyloxy, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
alkyloxyalkylheterocycloalkyl, heteroarylalkyl, cycloalkyloweralkyl, heterocycloalkyl-
loweralkyl, loweralkylheterocycloalkyl, arylloweralkyl, heteroarylloweralkyl, alkyloxy-
alkylheterocycloloweralkyl, or heteroarylloweralkyl;
R2 is hydrogen or loweralkyl;
R3 is hydrogen, halogen, loweralkyl, or loweralkoxy;
R4 is hydrogen or loweralkyl; and
R5, R5, R7, Rg and R9 are independently selected from hydrogen, halo,
loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy, haloloweralkyloxy,
loweralkylthio, haloloweralkylthio, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl; or
a pharmaceutically acceptable salt, ester or prodrug thereof.
50. A compound of Claim 49 wherein R4 is hydrogen.
51. A compound of Claim 49 wherein R4 is methyl.
52. A compound of Claim 49 wherein R5, R^, R7, Rg and R9 are
independently selected from hydrogen, chloro, fluoro, methyl, ethyl, propyl, iso-pvopyl,
butyl, f^rf-butyl, cyano, hydroxy, methyloxy, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, acetyl, and substituted or unsubstituted phenyl, phenyloxy, furyl,
tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, trifluoromethylpiperidinyl, thiophenyl,
piperazinyl, and morpholinyL
53. A compound of Claim 49 wherein Rj has the structure:
0
-177-
wo 2005/037273
PCT/US2004/034 1 79
(CH2)n
Rl2
wherein n is 0^ 1, 2^ 3 or 4;
r is 1 or 2;
X4 is -CH- or N
RlO and R12 are independently selected from hydrogen, halo, loweralkyl,
haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkyl-
sulfonyl, haloloweralkylsulfonyl, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl; and
Rj I is hydrogen, loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy,
haloloweralkyloxy, loweralkyloxyloweralkyl, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl.
54. A compound of Claim 53 wherein n is 1 .
55. A compound of Claim 53 wherein Rio and Rx2 are hydrogen or
loweralkyl.
56. A compound of Claim 53 wherein R^ i is loweralkyl.
57. A compound of the formula (VI):
(CH2)n,
N
R
10
N
R11
R12
(VI)
R2 is hydrogen or loweralkyl;
R3 is hydrogen, halogen, loweralkyl, or loweralkoxy;
R4 is hydrogen or loweralkyl; and
R5, R^, R7, Rs and R9 are independently selected from hydrogen, halo,
loweralkyl, cyano, hydroxy, haloloweralkyl, loweralkyloxy, haloloweralkyloxy.
-178-
wo 2005/037273
PCT/US2004/034179
loweralkylthio, haloloweralkylthio, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl;
n is 0, 1, 2, 3 or 4;
RjO and axe independently selected JBrom hydrogen, halo, loweralkyl,
haloloweralkyl, hydroxyloweralkyl, loweralkyloxy, haloloweralkyloxy, loweralkyl-
sulfonyl, haloloweralkylsulfonyl, and substituted or imsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl; and
Rl I is hydrogen, loweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkyloxy,
haloloweralkyloxy, loweralkyloxyloweralkyl, and substituted or unsubstituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl or
a pharmaceutically acceptable salt, ester or prodrug thereof.
58. A compound of Claim 57 wherein A compound of Claim 49 wherein R4 is
hydrogen.
59. A compound of Claim 57 wherein R4 is methyl.
60. A compoimd of Claim 57 wherein R5, R5, Ry, R3 and R9 are
independently selected from hydrogen, chloro, fluoro, methyl, ethyl, propyl, z^-o-propyl,
butyl, /er/-butyl, cyano, hydroxy, methyloxy, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, acetyl, and substituted or unsubstituted phenyl, phenyloxy, furyl,
tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, trifluoromethylpiperidinyl, thiophenyl,
piperazinyl, and morpholinyl.
61. A compound of Claim 57 wherein wherein n is 1 .
62. A compound of Claim 57 wherein wherein and R22 are hydrogen or
loweralkyl.
63. The compound of Claim 57 which is 2-(4-ethylpiperazin-l-yl)-N-{4-[(2-
{ [2-fluoro-5 -(trifluoromethyl)phenyl] amino } - 1 -methyl- 1 H-benzimidazol-5 -yl)oxy] -
pyridin-2-yl } acetamide.
-179-
wo 2005/037273
PCT/US2004/034179
64. A composition comprising an amount of a compound of claims 1, 13, 27,
38, 49, 57 or 63 effective to inhibit Raf activity in a human or animal subject when
administered thereto, together with a pharmaceutically acceptable carrier.
65. A composition of Claim 64 which further comprises at least one additional
agent for tlie treatment of cancer.
66. A composition of Claim 65 in which the at least one additional agent for
the treatment of cancer is selected from dacarbazine, irinotecan, topotecan, gemcitabine,
5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide,
vinca alkaloids, imatinib, anthracyclines, rituximab and trastuzumab.
67. A method of inhibiting Raf kinase activity in a hmnan or animal subject,
comprising administering to the human or animal subject a composition comprising an
amoimt of a compoimd of claims 1, 13, 27, 38, 49, 57 or 63 effective to inhibit Raf kinase
activity in the human or animal subject.
68. A method for treating a cancer disorder in a human or animal subject,
comprising administering to the human or animal subject a composition comprising an
amount of a compoxmd of claims 1, 13, 27, 38, 49, 57 or 63 effective to inhibit Raf kinase
activity in the human or animal subject.
69. A method of Claim 68 wherein said cancer is melanoma, papillary thyroid
cancer, cholangiocarcinoma, gallbladder carcinoma, colorectal cancer, lung cancer,
pancreatic cancer, lexakemia, prostate cancer, ovarian cancer, breast cancer, or lung
cancer.
70. A method of claim 68 which further comprises administering to the human
or animal subject at least one additional agent for the treatment of cancer.
71. A method of claim 70 in which the at least one additional agent for the
treatment of cancer is selected from dacarbazine, irinotecan, topotecan, gemcitabine, 5-
fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide,
vinca alkaloids, imatinib, anthracyclines, rituximab and trastuzimiab.
-180-
wo 2005/037273
PCT/US2004/034179
72. A method for treating a hormone dependent cancer disorder in a huirtan or
animal subject, comprising administering to the human or animal subject a composition
comprising an amount of a compound of claims 1, 13, 27, 38, 49, 57 or 63 effecti've to
inhibit Raf kinase activity in the hiiman or animal subject.
73. A method of claim 72 wherein the hormone dependent cancer is breast
cancer or prostate cancer.
74. A method of claim 72 which further comprises administering to the hixman
or animal subj ect at least one additional agent for the treatment of cancer.
75. A method of claim 74 in which the at least one additional agent far the
treatment of cancer is selected from dacarbazine, irinotecan, topotecan, gemcitabime, 5-
fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide,
vinca alkaloids, imatinib, anthracyclines, rituximab and trastuzumab.
76. A method for treating a hematological cancer disorder in a human or
animal subject, comprising administering to the human or animal subject a composition
comprising an amount of a compound of claims 1, 13, 27, 38, 49, 57 or 63 effecti-ve to
inhibit Raf kinase activity in the hioman or animal subj ect.
77. A method of claim 76 which further comprises administering to the homan
or animal subject at least one additional agent for the treatment of cancer.
78. A method of claim 77 in which the at least one additional agent for the
treatment of cancer is selected from dacarbazine, irinotecan, topotecan, gemcitabiae, 5-
fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide,
vinca alkaloids, imatinib, anthracyclines, rituximab and trastuzumab.
79. A compound of claims 1, 13, 27, 38, 49, 57 or 63 for use a.s a
pharmaceutical.
80. Use of a compound of claims 1, 13, 27, 38, 49, 57 or 63 in the
manufacture of a medicament for the treatment of cancer.
-181-
IN
NATIONAL SEARCH REPORT
Inte
ifl^bna^ Application No
PCT/US2004/034179
A. CLASSIFICATION OF SUBJECT MATTER
IPC 7 A61K31/4184 A61K31/428 C07D401/12 C07D405/14 C07D401/14
C07D417/12 C07D409/14 C07D413/14 A61P35/00
According to International Patent Classification (IPC) or to both national classification and IPC
B. FIELDS SEARCHED
Minimum documentation searched {classification system followed by classification symbols)
IPC 7 C07D
Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
Electronic data base consulted during the international search (name of data base and, where practical, search terms used)
EPO-Internal , WPI Data, PAJ, CHEM ABS Data
a DOCUMENTS CONSIDERED TO BE RELEVANT
Category
Citation of document, with indication, where appropriate, of the relevant passages
Relevant to claim No.
wo 03/082272 Al (CHIRON CORPORATION;
RENHOWE, PAUL, A; RAMURTHY, SAVITHRI;
AMIRI, PAYMA) 9 October 2003 (2003-10-09)
claims 1,74
1-80
WO 02/094808 Al (SMITHKLINE BEECHAM P.L.C;
DEAN, DAVID, KENNETH; TAKLE, ANDREW,
KENNETH) 28 November 2002 (2002-11-28)
claim 1
page 1, lines 3-24
1-80
Further documents are listed in the continuation of box C.
ID
Patent family members are listed in annex.
° Special categories of cited documents :
"A" document defining the general state of the art which Is not
considered to be of particular relevance
*'E" earlier document but published on or after the International
filing date
"L" document which may throw doubts on priority claim(s) or
which is cited to establish the publication date of another
citation or other special reason (as specified)
"O" document referring to an oral disclosure, use, exhibition or
other means
document published prior to the international filing dale but
later than the priority date claimed
IIQIt
T " later document published after the International filing date
or priority date and not in conflict with the application but
cited to understand the principle or theory underlying the
invention
X" document of particular relevance; the claimed invention
cannot be considered novel or cannot be considered to
involve an inventive step when the document Is taken alone
document of particular relevance; the claimed invention
cannot be considered to Involve an inventive step when the
document is combined with one or more other such docu-
ments, such combination being obvious to a person skilled
in the art.
&" document member of the same patent family
"Vit
Date of the actual completion of the international search
25 January 2005
Name and mailing address of the ISA
European Patent Office, P.B. 5818 Patentlaan 2
NL - 2280 HV Rijswljk
Tel. (+31-70) 340-2040, Tx, 31 651 epo nl,
Fax: (+31-70) 340-3016
Date of mailing of the international search report
04/02/2005
Authorized officer
Bern Ion, L
Form PCT/ISA/210 (second sheet) (January 2004)
INTERNATIONAL SEARCH REPORT
^^romational application No.
PCT/US2004/034179
Box II Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet)
This International Search Report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:
1.
X
Claims Nos.: 67-78
because they relate to subject matter not required to be sGarched by this Authority, namely:
Although claims 67-78 are directed to a method of treatment of the
human/animal body, the search has been carried out and based on the alleged
effects of the compound/composition.
2.
Claims Mos.:
because they relate to parts of the international Application that do not comply with the prescribed requirements to such
an extent that no meaningful international Search can be carried out, specifically:
3. I I Claims Nos.:
because they are dependent claims and are not drafted In accordance with the second and third sentences of Rule 6.4(a).
Box III Observations where unity of Invention Is lacking (Continuation of Item 3 of first sheet)
This International Searching Authority found multiple Inventions in this International application, as follows:
1 . I As all required additional search fees were timely paid by the applicant, this International Search Report covers all
' ' searchable claims.
2.
As all searchable claims could be searched without effort justifying an additional fee, this Authority did not invite payment
of any additional fee.
As only some of the required additional search fees were timely paid by the applicant, this Internationa! Search Report
covers only those claims for which fees were paid, specifically claims Nos.:
No required additional search fees were timely paid by the applicant. Consequently, this International Search Report Is
restricted to the Invention first mentioned in the claims; it Is covered by claims Nos.:
Remark on Protest
The additional search fees were accompanied by the applicants protest.
I I No protest accompanied the payment of additional search fees.
Form PCT/ISA/210 {continuation of first sheet (2)) (January 2004)
INKRNATIONAL SEARCH REPORT
Information on patent family members
Patent document
cited in search report
Publication
date
^nteiljjjjP^nal Application No
PCT/US2004/034179
Patent family
member(s)
Publication
date
WO 03082272
Al
09-10-2003
US 2004087626 Al
US 2004122237 Al
06-05-2004
24-06-2004
WO 02094808 Al 28-11-2002 EP 1397354 Al 17-03-2004
JP 2004529967 T 30-09-2004
US 2004127496 Al 01-07-2004
Form PCT/ISA/210 (patent family annex) [January 2004)
Live Music Archive
Librivox Free Audio
Metropolitan Museum
Cleveland Museum of Art
Internet Arcade
Console Living Room
Books to Borrow
Open Library
TV News
Understanding 9/11